Nitrogen substituted biaryl purine derivatives as potent antiproliferative agents

ABSTRACT

The compounds of the present invention are 2,6,9-trisubstituted purine derivatives which are inhibitors of cyclin/cdk complexes. The compounds of the current invention also are potent inhibitors of human cellular proliferation. As such, the compounds of the present invention constitute pharmaceutical compositions with a pharmaceutically acceptable carrier. Such compounds are useful in treating a disorder mediated by elevated levels of cell proliferation in a mammal compared to a healthy mammal by administering to such mammal an effective amount of the compound. Examples of the compounds of the present invention are represented by the following chemical structures: 
                 
 
with X, Y, D, Q, V, A, R 1 , R 2 , R 3 , R 4 , and n 1  defined herein.

This application is a continuation of U.S. patent application Ser. No.09/950,543, filed Sep. 11, 2001, now U.S. Pat. No. 6,667,311, which ishereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds that are shown to be potentcyclin/cyclin dependent kinase (cdk) inhibitors. Compounds with theseproperties are shown to be potent inhibitors of cell growth andproliferation. Such compounds can be used to treat the followingconditions in mammals: rheumatoid arthritis, lupus, type 1 diabetes,multiple sclerosis, cancer, restenosis, gout and other proliferativediseases involving elevated levels of cell proliferation compared tohealthy mammals. Compounds of the present invention which are biarylsubstituted purine derivatives are shown to be potent antiproliferativeagents against a number of human transformed cell lines, and alsoinhibitors of human cyclin/cdk kinase complexes.

BACKGROUND OF THE INVENTION

Cellular Proliferation and Cancer.

The disruption of external or internal regulation of cellular growth canlead to uncontrolled proliferation and in cancer, tumor formation. Thisloss of control can occur at many levels and, indeed, does occur atmultiple levels in most tumors. Further, although tumor cells can nolonger control their own proliferation, they still must use the samebasic cellular machinery employed by normal cells to drive their growthand replication.

Cyclin Dependent Kinases and Cell Cycle Regulation.

Progression of the normal cell cycle from the G1 to S phase, and fromthe G2 phase to M phase is dependent on cdks (Sherr, C. J., Science274:1672-1677 (1996)). Like other kinases, cdks regulate molecularevents in the cell by facilitating the transfer of the terminalphosphate of adenosine triphosphate (ATP) to a substrate protein.Isolated cdks require association with a second subunit, called cyclins(Desai et al., Mol. Cell. Biol., 15:345-350 (1995)). Cyclins causeconformational changes at the cdk active site, allowing ATP access andinteraction with the substrate protein. The balance between its rates ofsynthesis and degradation controls the level of each cyclin at any pointin the cycle (Elledge, S. J., et al., Biochim. Biophys. Acta,1377:M61-M70 (1998)). The influences of cyclin/cdk activity on the cellcycle and cellular transformation are summarized in Table 1.

Abnormal Cyclin/cdk Activity in Cancer.

In a normal cell, interlocking pathways respond to the cell's externalenvironment and internal checkpoints monitor conditions within the cellto control the activity of cyclin/cdk complexes. A reasonable hypothesisis that the disruption of normal control of cyclin/cdk activity mayresult in uncontrolled proliferation. This hypothesis appears to hold ina number of tumor types in which cyclins are expressed at elevatedlevels (Table 1). Mutations in the genes encoding negative regulators(proteins) of cyclin/cdk activity are also found in tumors (Larsen,C.-J., Prog. Cell Cycle Res., 3:109-124 (1997)); (Kamb, A., Trends inGenetics, 11:136-140 (1995)). Members of the Cip family of cdkinhibitors form a ternary complex with the cyclin/cdk and requirebinding to cyclinA, cyclinE, or cyclinD (Hall, M., et al., Oncogene,11:1581-1588 (1995)). In contrast, Ink family members form a binarycomplex with cdk4 or cdk6 and prevent binding to cyclinD (Parry, D.; etal., EMBO J., 14:503-511 (1995)).

TABLE 1 Associations Among Cyclins and Cancers Cyclin Cell Cycle RoleAssociated cdk Cancer A S, G2 to M cdk1, cdk2 hepatocellular carcinoma(Wang, J.; et al., Oncogene 8: 1653-1656 (1992)) B1/B2 G2 to M cdk1 noneyet defined D1 G1 cdk4, cdk6 parathyroid adenoma (Motokura, T., et al.,Nature, 350: 512-515 (1991)) centrocytic B cell lymphoma (Withers, D.A., et al., Mol. Cell. Biol., 11: 4846- 4853 (1991)) esophagealcarcinoma (Jiang, W., et al., Cancer Res., 52: 2980-2983 (1992)) breastcancer (Dickson, C., et al., Cancer Lett., 90: 43-50 (1995)) squamouscell carcinoma (Bartkova, J., et al., Cancer Res., 55: 949-956 (1995))hepatocellular carcinoma (Nishida, N., et al., Cancer Res., 54:3107-3110 (1994)) D2 G1 cdk4, cdk6 colorectal carcinoma (Leach, F. S.,et al., Cancer Res., 53: 1986-1989 (1993)) E G1 to S cdk2 breast cancer(Keytomarsi, K., et al., Cancer Res., 54: 380-385 (1994)) gastriccarcinoma (Akama, Y.; et al., Jap. J. Cancer Res., 86: 617-621 (1995))colorectal carcinoma (Kitihara, K.; et al., Int. J. Cancer, 62: 25-28(1995))Inhibitors of Cyclin/cdk Complexes as Potential Anticancer Agents.

Tumors with elevated cyclin/cdk activity, whether from the overexpression of cyclins or the loss of an endogenous cdk inhibitor, areprime targets for potential therapies based on small molecule cyclin/cdkinhibitors. In fact, several small molecule inhibitors of cyclin/cdksare reported (Meijer, L., et al., “Progress in Cell Cycle Research,”Plenum Press: New York, 351-363 (1995)) and appear to bind at the ATPsite of the kinase. Some information is known about small moleculeinhibitors of other kinases, such as PKC (serine kinase) (Murray, K. J.et al., “Ann. Rep. Med. Chem.,” J. Bristol, Ed., Academic Press, Inc.:New York, Chapter 26 (1994)) and tyrosine kinases (Fantl, W. J., et al.,Ann. Rev. Biochem., 62:453 (1993); Burke, T. R., Drugs of the Future,17:119-1131 (1992); Dobrusin, E. M. et al., “Ann. Rep. Med. Chem,” J.Bristol, Ed., Academic Press Inc.: New York, Chapter 18 (1992); Spence,P., Curr. Opin. Ther. Patents, 3:3 (1993)). A number of known inhibitorswere obtained from commercial sources or were synthesized by literatureprocedures.

Purine Compounds as Cyclin/cdk Inhibitors.

There are several reports of 2,6-diamino substituted purine derivativesas cyclin/cdk inhibitors and as inhibitors of cellular proliferation.Among those are reports by U.S. Pat. No. 5,583,137 to Coe, et al.,olomoucine (Vesely, J., et al., Eur. J. Biochem., 224:771-786 (1994)),roscovitine (Meijer, L., Eur. J. Biochem., 243:527-536 (1997)), WO97/16452 to Zimmerman, Imbach, P., et al., Bioorg. Med. Chem. Lett.,9:91-96 (1999), Norman, T. C., et al., J. Amer. Chem. Soc.,118:7430-7431 (1996), Gray, N. S., et al., Tetrahedron Lett.,38:1161-1164 (1997), Gray, N. S., et al., Science, 281:533-538 (1998),WO 98/05335 to Lum, et al., Schow, S. R., et al., Bioorg. Med. Chem.Lett, 7:2697-2702 (1997), U.S. Pat. No. 5,886,702 to Mackman, et al.,Nugiel, D. A., et al., J. Org. Chem., 62:201-203 (1997), and Fiorini, M.T. et al., Tetrahedron Lett., 39:1827-1830 (1998). Many of thesereported compounds are shown to inhibit cyclin/cdk complexes and havemodest cellular proliferation inhibition properties.

The compounds of the present invention are shown to have far superiorbiological activities as cyclin/cdk complex inhibitors as well asinhibitors of cellular proliferation compared to those previouslyreported. In fact, the art (e.g., Fiorini, M. T. et al., TetrahedronLett., 39:1827-1830 (1998)) teaches away from compounds of thisinvention, claiming lack of cellular proliferation inhibition.

SUMMARY OF THE INVENTION

The compounds of the present invention are 2,6,9-trisubstituted purinederivatives which are inhibitors of cyclin/cdk complexes. The compoundsof the current invention also are potent inhibitors of human cellularproliferation. As such, the compounds of the present inventionconstitute pharmaceutical compositions with a pharmaceuticallyacceptable carrier. Such compounds are useful in treating conditions ina mammal mediated by elevated levels of cell proliferation compared to ahealthy mammal by administering to such mammal an effective amount ofthe compound.

In one embodiment, the compounds of the present invention arerepresented by the chemical structure found in Formula I

wherein:

-   R₁ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₆-straight chain alkyl;    -   C₂-C₆-straight alkenyl chain;    -   C₃-C₆-branched alkyl chain;    -   C₃-C₆-branched alkenyl chain;    -   C₃-C₇-cycloalkyl;    -   CH₂—(C₃-C₇-cycloalkyl);    -   CH₂CF₃;    -   CH₂CH₂CF₃; and    -   CH(CF₃)₂;-   the combination of X, D, and Q are either:    -   D=Q=N, and X=CH; or    -   D=X=N, and Q=CH; or    -   Q=X=N, and D=CH; or    -   Q=N, and D=X=CH;-   V=NH;    -   O;    -   S; or    -   CH₂;-   R₂=phenyl;    -   substituted phenyl, wherein the substituents (1-2 in number) are        in any position and are independently selected from the group        consisting of R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂,        OC(O)CH₃, NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl,        and C(O)NHCHR₁CH₂OH;    -   1-naphthyl;    -   2-naphthyl;    -   heterocycles selected from the group consisting of:        -   2-pyridyl;        -   3-pyridyl;        -   4-pyridyl;        -   2-pyrimidyl;        -   4-pyrimidyl;        -   5-pyrimidyl;        -   thiophene-2-yl;        -   thiophene-3-yl;        -   2-furanyl;        -   3-furanyl;        -   oxazol-2-yl;        -   oxazol-4-yl;        -   oxazol-5-yl;        -   thiazol-2-yl;        -   thiazol-4-yl;        -   thiazol-5-yl;        -   imidazol-2-yl;        -   imidazol-4-yl;        -   pyrazol-3-yl;        -   pyrazol-4-yl;        -   isoxazol-3-yl;        -   isoxazol-4-yl;        -   isoxazol-5-yl;        -   isothiazol-3-yl;        -   isothiazol-4-yl;        -   isothiazol-5-yl;        -   1,3,4-thiadiazol-2-yl;        -   benzo[b]furan-2-yl;        -   benzo[b]thiophene-2-yl;        -   2-pyrrolyl;        -   3-pyrrolyl;        -   1,3,5-triazin-2-yl;        -   pyrazin-2-yl;        -   pyridazin-3-yl;        -   pyridazin-4-yl;        -   2-quinolinyl;        -   3-quinolinyl;        -   4-quinolinyl;        -   1-isoquinolinyl;        -   3-isoquinolinyl; and        -   4-isoquinolinyl; or    -   substituted heterocycle, wherein the substituents (1-2 in        number) are in any position and are independently selected from        the group consisting of Br, Cl, F, R₁, and C(O)CH₃;-   R₃ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph; and    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;-   R₄=H;    -   C₁-C₄-straight chain alkyl; or    -   C₃-C₄-branched chain alkyl;-   R₃ and R₄ can be linked together by a carbon chain to form with    intervening atoms a 5-8-membered saturated or unsaturated ring;-   n₁=0-3;-   n=0-3;-   A=CH₂;    -   (CH₂)₂;    -   (CH₂)₃;    -   OCH₂CH₂; or    -   CHCH₃;-   Y=H;    -   OR₁;    -   N(R₁)₂;    -   N(R₁)C(O)R₃;    -   N(R₁)C(O)R₅;    -   N(R₁)C(O)CH(R₆)NH₂;    -   N(R₁)SO₂R₃;    -   N(R₁)C(O)NHR₃; or    -   N(R₁)C(O)OR₆;-   R₅=C₃-C₇-cycloalkyl;-   R₆=C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph; or    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;        or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention is directed to a compound of thefollowing formula:

wherein:

-   R₁ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₆-straight chain alkyl;    -   C₂-C₆-straight alkenyl chain;    -   C₃-C₆-branched alkyl chain;    -   C₃-C₆-branched alkenyl chain;    -   C₃-C₇-cycloalkyl;    -   CH₂—(C₃-C₇-cycloalkyl);    -   CH₂CF₃;    -   CH₂CH₂CF₃; and    -   CH(CF₃)₂;-   the combination of X, D, and Q are either:    -   D=Q=N, and X=CH; or    -   D=X=N, and Q=CH; or    -   Q=X=N, and D=CH; or    -   Q=N, and D=X=CH;-   V=NH;    -   O;    -   S; or    -   CH₂;-   R₂=phenyl;    -   substituted phenyl, wherein the substituents (1-2 in number) are        in any position and are independently selected from the group        consisting of R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂,        OC(O)CH₃, NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl,        and C(O)NHCHR₁CH₂OH;    -   1-naphthyl;    -   2-naphthyl;    -   heterocycles selected from the group consisting of:        -   2-pyridyl;        -   3-pyridyl;        -   4-pyridyl;        -   2-pyrimidyl;        -   4-pyrimidyl;        -   5-pyrimidyl;        -   thiophene-2-yl;        -   thiophene-3-yl;        -   2-furanyl;        -   3-furanyl;        -   oxazol-2-yl;        -   oxazol-4-yl;        -   oxazol-5-yl;        -   thiazol-2-yl;        -   thiazol-4-yl;        -   thiazol-5-yl;        -   imidazol-2-yl;        -   imidazol-4-yl;        -   pyrazol-3-yl;        -   pyrazol-4-yl;        -   isoxazol-3-yl;        -   isoxazol-4-yl;        -   isoxazol-5-yl;        -   isothiazol-3-yl;        -   isothiazol-4-yl;        -   isothiazol-5-yl;        -   1,3,4-thiadiazol-2-yl;        -   benzo[b]furan-2-yl;        -   benzo[b]thiophene-2-yl;        -   2-pyrrolyl;        -   3-pyrrolyl;        -   1,3,5-triazin-2-yl;        -   pyrazin-2-yl;        -   pyridazin-3-yl;        -   pyridazin-4-yl;        -   2-quinolinyl;        -   3-quinolinyl;        -   4-quinolinyl;        -   1-isoquinolinyl;        -   3-isoquinolinyl; and        -   4-isoquinolinyl; or    -   substituted heterocycle, wherein the substituents (1-2 in        number) are in any position and are independently selected from        the group consisting of Br, Cl, F, R₁, and C(O)CH₃;-   n=0-3;-   A=CH₂;    -   (CH₂)₂;    -   (CH₂)₃;    -   OCH₂CH₂; or    -   CHCH₃;-   Y=H;    -   OR₁;    -   N(R₁)₂;    -   N(R₁)C(O)R₃;    -   N(R₁)C(O)R₅;    -   N(R₁)C(O)CH(R₆)NH₂;    -   N(R₁)SO₂R₃;    -   N(R₁)C(O)NHR₃; or    -   N(R₁)C(O)OR₆;-   R₃ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph; and    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;-   R₅=C₃-C₇-cycloalkyl;-   R₆=C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl; or    -   C₂-C₄-alkenyl chain;        or a pharmaceutically acceptable salt thereof.

The present invention is also directed to a process for preparation of apurine derivative compound of the formula:

wherein:

-   R₁ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₆-straight chain alkyl;    -   C₂-C₆-straight alkenyl chain;    -   C₃-C₆-branched alkyl chain;    -   C₃-C₆-branched alkenyl chain;    -   C₃-C₇-cycloalkyl;    -   CH₂—(C₃-C₇-cycloalkyl);    -   CH₂CF₃;    -   CH₂CH₂CF₃; and    -   CH(CF₃)₂;-   the combination of X, D, and Q are either:    -   D=Q=N, and X=CH; or    -   D=X=N, and Q=CH; or    -   Q=—X=N, and D=CH; or    -   Q=N, and D=X=CH;-   V=NH;    -   O;    -   S; or    -   CH₂;-   R₂=phenyl;    -   substituted phenyl, wherein the substituents (1-2 in number) are        in any position and are independently selected from the group        consisting of R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂,        OC(O)CH₃, NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl,        and C(O)NHCHR₁CH₂OH;    -   1-naphthyl;    -   2-naphthyl;    -   heterocycles selected from the group consisting of:        -   2-pyridyl;        -   3-pyridyl;        -   4-pyridyl;        -   2-pyrimidyl;        -   4-pyrimidyl;        -   5-pyrimidyl;        -   thiophene-2-yl;        -   thiophene-3-yl;        -   2-furanyl;        -   3-furanyl;        -   oxazol-2-yl;        -   oxazol-4-yl;        -   oxazol-5-yl;        -   thiazol-2-yl;        -   thiazol-4-yl;        -   thiazol-5-yl;        -   imidazol-2-yl;        -   imidazol-4-yl;        -   pyrazol-3-yl;        -   pyrazol-4-yl;        -   isoxazol-3-yl;        -   isoxazol-4-yl;        -   isoxazol-5-yl;        -   isothiazol-3-yl;        -   isothiazol-4-yl;        -   isothiazol-5-yl;        -   1,3,4-thiadiazol-2-yl;        -   benzo[b]furan-2-yl;        -   benzo[b]thiophene-2-yl;        -   2-pyrrolyl;        -   3-pyrrolyl;        -   1,3,5-triazin-2-yl;        -   pyrazin-2-yl;        -   pyridazin-3-yl;        -   pyridazin-4-yl;        -   2-quinolinyl;        -   3-quinolinyl;        -   4-quinolinyl;        -   1-isoquinolinyl;        -   3-isoquinolinyl; and        -   4-isoquinolinyl; or    -   substituted heterocycle, wherein the substituents (1-2 in        number) are in any position and are independently selected from        the group consisting of Br, Cl, F, R₁, and C(O)CH₃;-   R₃ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph; and    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;-   R₄=H;    -   C₁-C₄-straight chain alkyl; or    -   C₃-C₄-branched chain alkyl;-   R₃ and R₄ can be linked together by a carbon chain to form with    intervening atoms a 5-8-membered saturated or unsaturated ring;-   n₁=0-3;-   n=0-3;-   A=CH₂;    -   (CH₂)₂;    -   (CH₂)₃;    -   OCH₂CH₂; or    -   CHCH₃;-   Y=H;    -   OR₁;    -   N(R₁)₂;    -   N(R₁)C(O)R₃;    -   N(R₁)C(O)R₅;    -   N(R₁)C(O)CH(R₆)NH₂;    -   N(R₁)SO₂R₃;    -   N(R₁)C(O)NHR₃; or    -   N(R₁)C(O)OR₆;-   R₅=C₃-C₇-cycloalkyl;-   R₆=C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph; or    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;        or a pharmaceutically acceptable salt thereof, said process        comprising:    -   reacting a first intermediate compound of the formula:    -    where Z=Br or I        with a compound of the formula: R₂—B(OH)₂, R₂—Sn(n-Bu)₃, or        R₂—Sn(Me)₃, or mixtures thereof, under conditions effective to        form the purine derivative compound.

Another aspect of the present invention is directed to a process forpreparation of a purine derivative compound of the formula:

wherein:

-   R₁ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₆-straight chain alkyl;    -   C₂-C₆-straight alkenyl chain;    -   C₃-C₆-branched alkyl chain;    -   C₃-C₆-branched alkenyl chain;    -   C₃-C₇-cycloalkyl;    -   CH₂—(C₃-C₇-cycloalkyl);    -   CH₂CF₃;    -   CH₂CH₂CF₃; and    -   CH(CF₃)₂;-   the combination of X, D, and Q are either:    -   D=Q=N, and X=CH; or    -   D=X=N, and Q=CH; or    -   Q=X=N, and D=CH; or    -   Q=N, and D=X=CH;-   V=NH;    -   O;    -   S; or    -   CH₂;-   R₂=phenyl;    -   substituted phenyl, wherein the substituents (1-2 in number) are        in any position and are independently selected from the group        consisting of R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂,        OC(O)CH₃, NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl,        and C(O)NHCHR₁CH₂OH;    -   1-naphthyl;    -   2-naphthyl;    -   heterocycles selected from the group consisting of:        -   2-pyridyl;        -   3-pyridyl;        -   4-pyridyl;        -   2-pyrimidyl;        -   4-pyrimidyl;        -   5-pyrimidyl;        -   thiophene-2-yl;        -   thiophene-3-yl;        -   2-furanyl;        -   3-furanyl;        -   oxazol-2-yl;        -   oxazol-4-yl;        -   oxazol-5-yl;        -   thiazol-2-yl;        -   thiazol-4-yl;        -   thiazol-5-yl;        -   imidazol-2-yl;        -   imidazol-4-yl;        -   pyrazol-3-yl;        -   pyrazol-4-yl;        -   isoxazol-3-yl;        -   isoxazol-4-yl;        -   isoxazol-5-yl;        -   isothiazol-3-yl;        -   isothiazol-4-yl;        -   isothiazol-5-yl;        -   1,3,4-thiadiazol-2-yl;        -   benzo[b]furan-2-yl;        -   benzo[b]thiophene-2-yl;        -   2-pyrrolyl;        -   3-pyrrolyl;        -   1,3,5-triazin-2-yl;        -   pyrazin-2-yl;        -   pyridazin-3-yl;        -   pyridazin-4-yl;        -   2-quinolinyl;        -   3-quinolinyl;        -   4-quinolinyl;        -   1-isoquinolinyl;        -   3-isoquinolinyl; and        -   4-isoquinolinyl; or    -   substituted heterocycle, wherein the substituents (1-2 in        number) are in any position and are independently selected from        the group consisting of Br, Cl, F, R₁, and C(O)CH₃;-   R₃ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph; and    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;-   R₄=H;    -   C₁-C₄-straight chain alkyl; or    -   C₃-C₄-branched chain alkyl;-   R₃ and R₄ can be linked together by a carbon chain to form with    intervening atoms a 5-8-membered saturated or unsaturated ring;-   n₁=0-3;-   n=0-3;-   A=CH₂;    -   (CH₂)₂;    -   (CH₂)₃;    -   OCH₂CH₂; or    -   CHCH₃;-   Y=H;    -   OR₁;    -   N(R₁)₂;    -   N(R₁)C(O)R₃;    -   N(R₁)C(O)R₅;    -   N(R₁)C(O)CH(R₆)NH₂;    -   N(R₁)SO₂R₃;    -   N(R₁)C(O)NHR₃; or    -   N(R₁)C(O)OR₆;-   R₅=C₃-C₇-cycloalkyl;-   R₆=C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph; or    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;        or a pharmaceutically acceptable salt thereof, said process        comprising:-   reacting a first intermediate compound of the formula:    under reductive or hydrogenation conditions effective to form the    purine derivative compound.

Another aspect of the present invention is directed to a process forpreparation of a purine derivative compound of the formula:

wherein:

-   R₁ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₆-straight chain alkyl;    -   C₂-C₆-straight alkenyl chain;    -   C₃-C₆-branched alkyl chain;    -   C₃-C₆-branched alkenyl chain;    -   C₃-C₇-cycloalkyl;    -   CH₂—(C₃-C₇-cycloalkyl);    -   CH₂CF₃;    -   CH₂CH₂CF₃; and    -   CH(CF₃)₂;-   the combination of X, D, and Q are either:    -   D=Q=N, and X=CH; or    -   D=X=N, and Q=CH; or    -   Q=X=N, and D=CH; or    -   Q=N, and D=X=CH;-   V=NH;    -   O;    -   S; or    -   CH₂;-   R₂=phenyl;    -   substituted phenyl, wherein the substituents (1-2 in number) are        in any position and are independently selected from the group        consisting of R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂,        OC(O)CH₃, NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl,        and C(O)NHCHR₁CH₂OH;    -   1-naphthyl;    -   2-naphthyl;    -   heterocycles selected from the group consisting of:        -   2-pyridyl;        -   3-pyridyl;        -   4-pyridyl;        -   2-pyrimidyl;        -   4-pyrimidyl;        -   5-pyrimidyl;        -   thiophene-2-yl;        -   thiophene-3-yl;        -   2-furanyl;        -   3-furanyl;        -   oxazol-2-yl;        -   oxazol-4-yl;        -   oxazol-5-yl;        -   thiazol-2-yl;        -   thiazol-4-yl;        -   thiazol-5-yl;        -   imidazol-2-yl;        -   imidazol-4-yl;        -   pyrazol-3-yl;        -   pyrazol-4-yl;        -   isoxazol-3-yl;        -   isoxazol-4-yl;        -   isoxazol-5-yl;        -   isothiazol-3-yl;        -   isothiazol-4-yl;        -   isothiazol-5-yl;        -   1,3,4-thiadiazol-2-yl;        -   benzo[b]furan-2-yl;        -   benzo[b]thiophene-2-yl;        -   2-pyrrolyl;        -   3-pyrrolyl;        -   1,3,5-triazin-2-yl;        -   pyrazin-2-yl;        -   pyridazin-3-yl;        -   pyridazin-4-yl;        -   2-quinolinyl;        -   3-quinolinyl;        -   4-quinolinyl;        -   1-isoquinolinyl;        -   3-isoquinolinyl; and        -   4-isoquinolinyl; or    -   substituted heterocycle, wherein the substituents (1-2 in        number) are in any position and are independently selected from        the group consisting of Br, Cl, F, R₁, and C(O)CH₃;-   R₃ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph; and    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;-   R₄=H;    -   C₁-C₄-straight chain alkyl; or    -   C₃-C₄-branched chain alkyl;-   R₃ and R₄ can be linked together by a carbon chain to form with    intervening atoms a 5-8-membered saturated or unsaturated ring;-   n₁=0-3;-   n=0-3;-   A=CH₂;    -   (CH₂)₂;    -   (CH₂)₃;    -   OCH₂CH₂; or    -   CHCH₃;-   Y=H;    -   OR₁;    -   N(R₁)₂;    -   N(R₁)C(O)R₃;    -   N(R₁)C(O)R₅;    -   N(R₁)C(O)CH(R₆)NH₂;    -   N(R₁)SO₂R₃;    -   N(R₁)C(O)NHR₃; or    -   N(R₁)C(O)OR₆;-   R₅=C₃-C₇-cycloalkyl;-   R₆=C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph; or    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;        or a pharmaceutically acceptable salt thereof, said process        comprising:    -   reacting a first intermediate compound of the formula:        with a compound of the formula:-   where V₁=NH₂;    -   OH; or    -   SH;        under conditions effective to form the purine derivative        compound.

Another aspect of the present invention is directed to a process forpreparation of a purine derivative compound of the formula:

wherein:

-   R₁ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₆-straight chain alkyl;    -   C₂-C₆-straight alkenyl chain;    -   C₃-C₆-branched alkyl chain;    -   C₃-C₆-branched alkenyl chain;    -   C₃-C₇-cycloalkyl;    -   CH₂—(C₃-C₇-cycloalkyl);    -   CH₂CF₃;    -   CH₂CH₂CF₃; and    -   CH(CF₃)₂;-   the combination of X, D, and Q are either:    -   D=Q=N and X=CH; or    -   D=X=N and Q=CH; or    -   Q=X=N and D=CH; or    -   Q=N and D=X=CH;-   V=NH;    -   O;    -   S; or    -   CH₂;-   R₂=phenyl;    -   substituted phenyl, wherein the substituents (1-2 in number) are        in any position and are independently selected from the group        consisting of R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂,        OC(O)CH₃, NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl,        and C(O)NHCHR₁CH₂OH;    -   1-naphthyl;    -   2-naphthyl;    -   heterocycles selected from the group consisting of:        -   2-pyridyl;        -   3-pyridyl;        -   4-pyridyl;        -   2-pyrimidyl;        -   4-pyrimidyl;        -   5-pyrimidyl;        -   thiophene-2-yl;        -   thiophene-3-yl;        -   2-furanyl;        -   3-furanyl;        -   oxazol-2-yl;        -   oxazol-4-yl;        -   oxazol-5-yl;        -   thiazol-2-yl;        -   thiazol-4-yl;        -   thiazol-5-yl;        -   imidazol-2-yl;        -   imidazol-4-yl;        -   pyrazol-3-yl;        -   pyrazol-4-yl;        -   isoxazol-3-yl;        -   isoxazol-4-yl;        -   isoxazol-5-yl;        -   isothiazol-3-yl;        -   isothiazol-4-yl;        -   isothiazol-5-yl;        -   1,3,4-thiadiazol-2-yl;        -   benzo[b]furan-2-yl;        -   benzo[b]thiophene-2-yl;        -   2-pyrrolyl;        -   3-pyrrolyl;        -   1,3,5-triazin-2-yl;        -   pyrazin-2-yl;        -   pyridazin-3-yl;        -   pyridazin-4-yl;        -   2-quinolinyl;        -   3-quinolinyl;        -   4-quinolinyl;        -   1-isoquinolinyl;        -   3-isoquinolinyl; and        -   4-isoquinolinyl; or    -   substituted heterocycle, wherein the substituents (1-2 in        number) are in any position and are independently selected from        the group consisting of Br, Cl, F, R₁, and C(O)CH₃;-   R₃ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph; and    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;-   R₄=H;    -   C₁-C₄-straight chain alkyl; or    -   C₃-C₄-branched chain alkyl;-   R₃ and R₄ can be linked together by a carbon chain to form with    intervening atoms a 5-8-membered saturated or unsaturated ring;-   n₁=0-3;-   n=0-3;-   A=CH₂;    -   (CH₂)₂;    -   (CH₂)₃;    -   OCH₂CH₂; or    -   CHCH₃;-   Y=NR₁C(O)R₃;    -   NR₁C(O)R₅;    -   NR₁ SO₂R₃;    -   NR₁C(O)NHR₃; or    -   NR₁C(O)OR₆-   R₅=C₃-C₇-cycloalkyl;-   R₆=C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph; or    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;        or a pharmaceutically acceptable salt thereof;-   said process comprising:    -   reacting a first intermediate compound having the same formula        as the purine derivative compound except that Y=NHR₁, with        R₃COCl or R₅COCl or R₃SO₂Cl or R₃NCO or R₆OC(O)Cl under        conditions effective to form the purine derivative compound.

Yet another aspect of the present invention is directed to a process forpreparation of a purine derivative compound of the formula:

wherein:

-   R₁ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₆-straight chain alkyl;    -   C₂-C₆-straight alkenyl chain;    -   C₃-C₆-branched alkyl chain;    -   C₃-C₆-branched alkenyl chain;    -   C₃-C₇-cycloalkyl;    -   CH₂—(C₃-C₇-cycloalkyl);    -   CH₂CF₃;    -   CH₂CH₂CF₃; and    -   CH(CF₃)₂;-   the combination of X, D, and Q are either:    -   D=Q=N and X=CH; or    -   D=X=N and Q=CH; or    -   Q=X=N and D=CH; or    -   Q=N and D=X=CH;-   V=NH;    -   O;    -   S; or    -   CH₂;-   R₂=phenyl;    -   substituted phenyl, wherein the substituents (1-2 in number) are        in any position and are independently selected from the group        consisting of R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂,        OC(O)CH₃, NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl,        and C(O)NHCHR₁CH₂OH;    -   1-naphthyl;    -   2-naphthyl;    -   heterocycles selected from the group consisting of:        -   2-pyridyl;        -   3-pyridyl;        -   4-pyridyl;        -   2-pyrimidyl;        -   4-pyrimidyl;        -   5-pyrimidyl;        -   thiophene-2-yl;        -   thiophene-3-yl;        -   2-furanyl;        -   3-furanyl;        -   oxazol-2-yl;        -   oxazol-4-yl;        -   oxazol-5-yl;        -   thiazol-2-yl;        -   thiazol-4-yl;        -   thiazol-5-yl;        -   imidazol-2-yl;        -   imidazol-4-yl;        -   pyrazol-3-yl;        -   pyrazol-4-yl;        -   isoxazol-3-yl;        -   isoxazol-4-yl;        -   isoxazol-5-yl;        -   isothiazol-3-yl;        -   isothiazol-4-yl;        -   isothiazol-5-yl;        -   1,3,4-thiadiazol-2-yl;        -   benzo[b]furan-2-yl;        -   benzo[b]thiophene-2-yl;        -   2-pyrrolyl;        -   3-pyrrolyl;        -   1,3,5-triazin-2-yl;        -   pyrazin-2-yl;        -   pyridazin-3-yl;        -   pyridazin-4-yl;        -   2-quinolinyl;        -   3-quinolinyl;        -   4-quinolinyl;        -   1-isoquinolinyl;        -   3-isoquinolinyl; and        -   4-isoquinolinyl; or    -   substituted heterocycle, wherein the substituents (1-2 in        number) are in any position and are independently selected from        the group consisting of Br, Cl, F, R₁, and C(O)CH₃;-   R₃ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph; and    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;-   R₄=H;    -   C₁-C₄-straight chain alkyl; or    -   C₃-C₄-branched chain alkyl;-   R₃ and R₄ can be linked together by a carbon chain to form with    intervening atoms a 5-8-membered saturated or unsaturated ring;-   n₁=0-3;-   n=0-3;-   A=CH₂;    -   (CH₂)₂;    -   (CH₂)₃;    -   OCH₂CH₂; or    -   CHCH₃;-   Y=NHC(O)CH(R₆)NH₂;-   R₅=C₃-C₇-cycloalkyl;-   R₆=C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph; or    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;        or a pharmaceutically acceptable salt thereof;-   said process comprising:    -   reacting a first intermediate compound having the same formula        as the purine derivative compound except that Y is NH₂, with a        compound of the formula: PNHCH(R₆)CO₂H under conditions        effective to form the purine derivative compound after a        suitable deprotection strategy,        wherein-   P=C(O)OtBu;    -   C(O)OCH₂Ph;    -   Fmoc    -   Benzyl; or    -   Alloc.

The compounds of the present invention, as described in Formula I, showsignificantly improved growth inhibition of human transformed cell linesand/or cyclin/cdk inhibition relative to compounds of the prior art.These compounds have been demonstrated to be potent growth inhibitors indozens of human transformed cell lines. Olomoucine, a structurallyrelated purine derivative, is a poor human transformed cell growthinhibition agent with GI₅₀ values in the 20,000-100,000 nM range over60-transformed cell lines. By contrast, the compounds of the presentinvention demonstrate GI₅₀ values over 60-transformed cell lines in the<10-25,000 nM range, preferably in the <10-100 nM range over60-transformed cell lines, and, most preferably, <10 nM across 60-humantransformed cell lines. This finding is unexpected from the prior art,which specifically teaches that compounds of the present invention wouldnot be potent human transformed cell line growth inhibitors.

The R₂ group in Formula I imparts unexpected and significant improvementin growth inhibition in human transformed cell lines, while substitutionof various groups at R₃ and R₄ found in Formula I impart importantfeatures that contribute to cyclin/cdk inhibition and growth inhibitionof human transformed cell lines. Specifically, the combination of the R₂group and the substitutions within R₃ and R₄ result in compounds withsuperior biological activity. Compounds which are cyclin/cdk inhibitorsand/or human transformed cell line growth inhibitors have utility intreating human proliferative cellular disorders.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are represented by the chemicalstructure found in Formula I.

wherein:

-   R₁ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₆-straight chain alkyl;    -   C₂-C₆-straight alkenyl chain;    -   C₃-C₆-branched alkyl chain;    -   C₃-C₆-branched alkenyl chain;    -   C₃-C₇-cycloalkyl;    -   CH₂—(C₃-C₇-cycloalkyl);    -   CH₂CF₃;    -   CH₂CH₂CF₃; and    -   CH(CF₃)₂;-   the combination of X, D, and Q are either:    -   D=Q=N, and X=CH; or    -   D=X=N, and Q=CH; or    -   Q=X=N, and D=CH; or    -   Q=N, and D=X=CH;-   V=NH;    -   O;    -   S; or    -   CH₂;-   R₂=phenyl;    -   substituted phenyl, wherein the substituents (1-2 in number) are        in any position and are independently selected from the group        consisting of R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂,        OC(O)CH₃, NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl,        and C(O)NHCHR₁CH₂OH;    -   1-naphthyl;    -   2-naphthyl;    -   heterocycles selected from the group consisting of:        -   2-pyridyl;        -   3-pyridyl;        -   4-pyridyl;        -   2-pyrimidyl;        -   4-pyrimidyl;        -   5-pyrimidyl;        -   thiophene-2-yl;        -   thiophene-3-yl;        -   2-furanyl;        -   3-furanyl;        -   oxazol-2-yl;        -   oxazol-4-yl;        -   oxazol-5-yl;        -   thiazol-2-yl;        -   thiazol-4-yl;        -   thiazol-5-yl;        -   imidazol-2-yl;        -   imidazol-4-yl;        -   pyrazol-3-yl;        -   pyrazol-4-yl;        -   isoxazol-3-yl;        -   isoxazol-4-yl;        -   isoxazol-5-yl;        -   isothiazol-3-yl;        -   isothiazol-4-yl;        -   isothiazol-5-yl;        -   1,3,4-thiadiazol-2-yl;        -   benzo[b]furan-2-yl;        -   benzo[b]thiophene-2-yl;        -   2-pyrrolyl;        -   3-pyrrolyl;        -   1,3,5-triazin-2-yl;        -   pyrazin-2-yl;        -   pyridazin-3-yl;        -   pyridazin-4-yl;        -   2-quinolinyl;        -   3-quinolinyl;        -   4-quinolinyl;        -   1-isoquinolinyl;        -   3-isoquinolinyl; and        -   4-isoquinolinyl; or    -   substituted heterocycle, wherein the substituents (1-2 in        number) are in any position and are independently selected from        the group consisting of Br, Cl, F, R₁, and C(O)CH₃;-   R₃ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph; and    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;-   R₄=H;    -   C₁-C₄-straight chain alkyl; or    -   C₃-C₄-branched chain alkyl;-   R₃ and R₄ can be linked together by a carbon chain to form with    intervening atoms a 5-8-membered saturated or unsaturated ring;-   n₁=0-3;-   n=0-3;-   A=CH₂;    -   (CH₂)₂;    -   (CH₂)₃;    -   OCH₂CH₂; or    -   CHCH₃;-   Y=H;    -   OR₁;    -   N(R₁)₂;    -   N(R₁)C(O)R₃;    -   N(R₁)C(O)R₅;    -   N(R₁)C(O)CH(R₆)NH₂;    -   N(R₁)SO₂R₃;    -   N(R₁)C(O)NHR₃; or    -   N(R₁)C(O)OR₆;-   R₅=C₃-C₇-cycloalkyl;-   R₆=C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph; or    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;        or a pharmaceutically acceptable salt thereof.

More preferably, the compounds of the current invention are representedby the chemical structure found in Formula III.

wherein:

-   R₁ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₆-straight chain alkyl;    -   C₂-C₆-straight alkenyl chain;    -   C₃-C₆-branched alkyl chain;    -   C₃-C₆-branched alkenyl chain;    -   C₃-C₇-cycloalkyl;    -   CH₂—(C₃-C₇-cycloalkyl);    -   CH₂CF₃;    -   CH₂CH₂CF₃; and    -   CH(CF₃)₂;-   the combination of X, D, and Q are either:    -   D=Q=N, and X=CH; or    -   D=X=N, and Q=CH; or    -   Q=X=N, and D=CH; or    -   Q=N, and D=X=CH;-   V=NH;    -   O;    -   S; or    -   CH₂;-   R₂=phenyl;    -   substituted phenyl, wherein the substituents (1-2 in number) are        in any position and are independently selected from the group        consisting of R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂,        OC(O)CH₃, NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl,        and C(O)NHCHR₁CH₂OH;    -   1-naphthyl;    -   2-naphthyl;    -   heterocycles selected from the group consisting of:        -   2-pyridyl;        -   3-pyridyl;        -   4-pyridyl;        -   2-pyrimidyl;        -   4-pyrimidyl;        -   5-pyrimidyl;        -   thiophene-2-yl;        -   thiophene-3-yl;        -   2-furanyl;        -   3-furanyl;        -   oxazol-2-yl;        -   oxazol-4-yl;        -   oxazol-5-yl;        -   thiazol-2-yl;        -   thiazol-4-yl;        -   thiazol-5-yl;        -   imidazol-2-yl;        -   imidazol-4-yl;        -   pyrazol-3-yl;        -   pyrazol-4-yl;        -   isoxazol-3-yl;        -   isoxazol-4-yl;        -   isoxazol-5-yl;        -   isothiazol-3-yl;        -   isothiazol-4-yl;        -   isothiazol-5-yl;        -   1,3,4-thiadiazol-2-yl;        -   benzo[b]furan-2-yl;        -   benzo[b]thiophene-2-yl;        -   2-pyrrolyl;        -   3-pyrrolyl;        -   1,3,5-triazin-2-yl;        -   pyrazin-2-yl;        -   pyridazin-3-yl;        -   pyridazin-4-yl;        -   2-quinolinyl;        -   3-quinolinyl;        -   4-quinolinyl;        -   1-isoquinolinyl;        -   3-isoquinolinyl; and        -   4-isoquinolinyl; or    -   substituted heterocycle, wherein the substituents (1-2 in        number) are in any position and are independently selected from        the group consisting of Br, Cl, F, R₁, and C(O)CH₃;-   n=0-3;-   A=CH₂;    -   (CH₂)₂;    -   (CH₂)₃;    -   OCH₂CH₂; or    -   CHCH₃;-   Y=H;    -   OR₁;    -   N(R₁)₂;    -   N(R₁)C(O)R₃;    -   N(R₁)C(O)R₅;    -   N(R₁)C(O)CH(R₆)NH₂;    -   N(R₁)SO₂R₃;    -   N(R₁)C(O)NHR₃; or    -   N(R₁)C(O)OR₆;-   R₃ are the same or different and independently selected from the    group consisting of:    -   H;    -   C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph; and    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;-   R₅=C₃-C₇-cycloalkyl;-   R₆=C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl; or    -   C₂-C₄-alkenyl chain;        or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is directed to a method oftreating a mammal with a disorder mediated by elevated levels ofcellular proliferation comprising administering a therapeuticallyeffective amount of the compound of the present invention to the mammalunder conditions effective to treat the disorder mediated by elevatedlevels of cell proliferation.

The compounds of the present invention can be administered orally,parenterally, for example, subcutaneously, intravenously,intramuscularly, intraperitoneally, by intranasal instillation, or byapplication to mucous membranes, such as, that of the nose, throat, andbronchial tubes. They may be administered alone or with suitablepharmaceutical carriers, and can be in solid or liquid form such as,tablets, capsules, powders, solutions, suspensions, or emulsions.

Based on the results obtained in the standard pharmacological testprocedures described below, the compounds of the present invention areuseful as antineoplastic agents. More particularly, the compounds of thepresent invention are useful for inhibiting the growth of neoplasticcells, causing cell death of neoplastic cells, and eradicatingneoplastic cells. The compounds of the present invention are, therefore,useful for treating solid tumors, including sarcomas and carcinomas,such as astrocytomas, prostate cancer, breast cancer, small cell lungcancer, and ovarian cancer, leukemias, lymphomas, adult T-cellleukemia/lymphoma, and other neoplastic disease states.

In addition to the utilities described above, many of the compounds ofthe present invention are useful in the preparation of other compounds.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent, or with an assimilableedible carrier, or they may be enclosed in hard or soft shell capsules,or they may be compressed into tablets, or they may be incorporateddirectly with the food of the diet. For oral therapeutic administration,these active compounds may be incorporated with excipients and used inthe form of tablets, capsules, elixirs, suspensions, syrups, and thelike. Such compositions and preparations should contain at least 0.1% ofactive compound. The percentage of the compound in these compositionsmay, of course, be varied and may conveniently be between about 2% toabout 60% of the weight of the unit. The amount of active compound insuch therapeutically useful compositions is such that a suitable dosagewill be obtained. Preferred compositions according to the presentinvention are prepared so that an oral dosage unit contains betweenabout 1 and 250 mg of active compound.

The tablets, capsules, and the like may also contain a binder such asgum tragacanth, acacia, corn starch, or gelatin; excipients such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch, alginic acid; a lubricant such as magnesium stearate; and asweetening agent such as sucrose, lactose, or saccharin. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar, or both. A syrup may contain, in addition to activeingredient, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye, and flavoring such as cherry or orange flavor.

These active compounds may also be administered parenterally. Solutionsor suspensions of these active compounds can be prepared in watersuitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols, and mixtures thereof in oils. Illustrative oils are those ofpetroleum, animal, vegetable, or synthetic origin, for example, peanutoil, soybean oil, or mineral oil. In general, water, saline, aqueousdextrose and related sugar solution, and glycols such as, propyleneglycol or polyethylene glycol, are preferred liquid carriers,particularly for injectable solutions. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms, such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

The compounds of the present invention may also be administered directlyto the airways in the form of an aerosol. For use as aerosols, thecompounds of the present invention in solution or suspension may bepackaged in a pressurized aerosol container together with suitablepropellants, for example, hydrocarbon propellants like propane, butane,or isobutane with conventional adjuvants. The materials of the presentinvention also may be administered in a non-pressurized form such as ina nebulizer or atomizer.

General Synthetic Schemes

The compounds of the present invention can be prepared by conventionalmethods of organic synthesis practiced by those skilled in the art. Thegeneral reaction sequences outlined below are general methods useful forpreparing the compounds of the present invention and are not meant to belimiting in scope or utility.

Reaction of 2,6-dichloropurine (Formula IV) with various amines ofFormula V, many of which are commercially available or prepared byliterature methods or modifications of literature methods, in thepresence of a polar solvent, such as ethanol, provides purines ofFormula VI (General Flowsheet I, infra). Reaction of purines of FormulaVI with alkyl halides (R₁-Z) in the presence of a base such as potassiumcarbonate provides N1-alkylated purines of Formula VII. Chloridedisplacement of N1-alkylated purines of Formula VII with amines, thiolsor alcohols of structure Formula VIII, either in neat solution or in aninert solvent such as ethanol or butanol, with or without a base such assodium hydride as appropriate, at an appropriate temperature providespurines of Formula IX (V=NH, O, S). Transition metal-mediatedcross-coupling reaction of purines of Formula IX with boronic acid(R₂—B(OH)₂) or tin reagents (R₂—Sn(n-Bu)₃ or R₂—SnMe₃) provides purinesof Formula X (V=NH, O, S). If in Formula X (Y=NH₂), then subsequentreaction of Formula X (Y=NH₂) with acid chloride (R₃COCl), or sulfonylchloride (R₃SO₂Cl), or isocyanate (R₃NCO), or chloroformate (ClC(O)OR₆)reagents provides purines of Formula XI wherein Y=NHC(O)R₃, NHSO₂R₃, orNHC(O)NHR₃, or NHC(O)OR₆, respectively. On the other hand, if in FormulaX, Y already is OR₁ or NHC(O)R₃ or NHSO₂R₃ or NHC(O)NHR₃ or NHC(O)OR₆,as a result of what Y started out as in Formula VIII, then this laststep is unnecessary.

Reaction of purines of Formula VII, with alkenyl tin reagents of FormulaXII, which are prepared by conventional methods described in theliterature, in the presence of a transition metal catalyst, such asPd(0), provides purines of Formula XIII (General Flowsheet II, infra).Subsequent reaction of purines of Formula XIII with boronic acid(R₂—B(OH)₂) or tin reagents (R₂—Sn(n-Bu)₃ or R₂—SnMe₃) in the presenceof a transition metal catalyst, such as Pd(0), provides purines ofFormula XV. Alternatively, by switching the order of reactions dependenton the precise reactivity of the purine of Formula VII, reaction ofpurines of Formula VII with boronic acid (R₂—B(OH)₂) or tin reagents(R₂—Sn(n-Bu)₃ or R₂—SnMe₃) in the presence of a transition metalcatalyst, such as Pd(0), provides purines of Formula XIV. Subsequentreaction of purines of Formula XIV, with alkenyl tin reagents of FormulaXII, which are prepared by conventional methods described in theliterature, in the presence of a transition metal catalyst, such asPd(0), provides purines of Formula XV. Finally reduction of the olefinwithin Formula XV provides purines of Formula X (V=CH₂).

Definitions of the groups include:

-   Z=Br;    -   I;-   V=NH₂;    -   OH;    -   SH;-   R₁ are the same or different and independently selected from:    -   H;    -   C₁-C₆-straight chain alkyl;    -   C₂-C₆-straight alkenyl chain;    -   C₃-C₆-branched alkyl chain;    -   C₃-C₆-branched alkenyl chain;    -   C₃-C₇-cycloalkyl;    -   CH₂—(C₃-C₇-cycloalkyl);    -   CH₂CF₃;    -   CH₂CH₂CF₃;    -   CH(CF₃)₂;-   the combination of X, D, and Q are selected from:    -   D=Q=N, and X=CH;    -   D=X=N, and Q=CH;    -   Q=X=N, and D=CH;    -   Q=N, and D=X=CH;-   V=NH;    -   O;    -   S;    -   CH₂;-   R₂ can be in any position on the ring and selected from:    -   phenyl;    -   substituted phenyl, wherein the substituents (1-2 in number) are        in any position and are independently selected from R₁, OR₁,        SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl, Br,        CF₃, C(O)R₁, C(O)NHR₁, phenyl, C(O)NHCHR₁CH₂OH;    -   1-naphthyl;    -   2-naphthyl;    -   heterocycles including:        -   2-pyridyl;        -   3-pyridyl;        -   4-pyridyl;        -   2-pyrimidyl;        -   4-pyrimidyl;        -   5-pyrimidyl;        -   thiophene-2-yl;        -   thiophene-3-yl;        -   2-furanyl;        -   3-furanyl;        -   oxazol-2-yl;        -   oxazol-4-yl;        -   oxazol-5-yl;        -   thiazol-2-yl;        -   thiazol-4-yl;        -   thiazol-5-yl;        -   imidazol-2-yl;        -   imidazol-4-yl;        -   pyrazol-3-yl;        -   pyrazol-4-yl;        -   isoxazol-3-yl;        -   isoxazol-4-yl;        -   isoxazol-5-yl;        -   isothiazol-3-yl;        -   isothiazol-4-yl;        -   isothiazol-5-yl;        -   1,3,4-thiadiazol-2-yl;        -   benzo[b]furan-2-yl;        -   benzo[b]thiophene-2-yl;        -   2-pyrrolyl;        -   3-pyrrolyl;        -   1,3,5-triazin-2-yl;        -   pyrazin-2-yl;        -   pyridazin-3-yl;        -   pyridazin-4-yl;        -   2-quinolinyl;        -   3-quinolinyl;        -   4-quinolinyl;        -   1-isoquinolinyl;        -   3-isoquinolinyl;        -   4-isoquinolinyl;    -   substituted heterocycle, wherein the substituents (1-2 in        number) are in any position and are independently selected from        Br, Cl, F, R₁, C(O)CH₃;-   R₃ are the same or different and independently selected from:    -   H;    -   C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph;    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;-   R₄=H;    -   C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;-   R₃ and R₄ can be linked together by a carbon chain to form a    5-8-membered saturated or unsaturated ring;-   n₁=0-3;-   n=0-3;-   A=(CH₂);    -   (CH₂)₂;    -   (CH₂)₃;    -   (OCH₂CH₂);    -   (CHCH₃);-   Y=H;    -   OR₁;    -   N(R₁)₂;    -   N(R₁)C(O)R₃;    -   N(R₁)C(O)R₅;    -   N(R₁)C(O)CH(R₆)NH₂;    -   N(R₁)SO₂R₃;    -   N(R₁)C(O)NHR₃;    -   N(R₁)C(O)OR₆;-   R₅=C₃-C₇-cycloalkyl;-   R₆=C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph;    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂.        Additional, general non-limiting syntheses of compounds of the        present invention of Formula X and Formula XI are shown below in        General Flowsheet III.        Reaction of various amines of Formula V, many of which are        commercially available or prepared by literature methods or        modifications of literature methods, with boronic acid        (R₂—B(OH)₂) or tin reagents (R₂—Sn(n-Bu)₃) or (R₂—SnMe₃) in the        presence of a transition metal catalyst, such as Pd(0), provides        biaryl amines of Formula XVII. Reaction of 2,6-dichloropurine        (Formula IV) with various amines of Formula XVII, in the        presence of a polar solvent, such as ethanol, provides purines        of Formula XVIII. Reaction of purines of Formula XVIII with        alkyl halides (R₁-Z) in the presence of a base such as potassium        carbonate provides N1-alkylated purines of Formula XIV. Chloride        displacement of N1-alkylated purines of Formula XIV with amines,        thiols or alcohols of Formula VIII, either in neat solution or        in an inert solvent such as ethanol or butanol, with or without        a base such as sodium hydride as appropriate, at an appropriate        temperature provides purines of Formula X (V=NH, O, S). If in        Formula X (Y=NH₂), then subsequent reaction of Formula X (Y=NH₂)        with acid chloride (R₃COCl), or sulfonyl chloride (R₃SO₂Cl), or        isocyanate (R₃NCO), or chloroformate (ClC(O)OR₆) reagents        provides purines of Formula XI wherein Y=NHC(O)R₃, NHSO₂R₃, or        NHC(O)NHR₃, or NHC(O)OR₆, respectively. On the other hand, if in        Formula X, Y already is OR₁ or NHC(O)R₃ or NHSO₂R₃ or NHC(O)NHR₃        or NHC(O)OR₆, as a result of what Y started out as in Formula        VIII, then this last step is unnecessary.        Definitions of the groups include:-   Z=Br;    -   I;-   V₁=NH₂;    -   OH;    -   SH;-   R₁ are the same or different and independently selected from:    -   H;    -   C₁-C₆-straight chain alkyl;    -   C₂-C₆-straight alkenyl chain;    -   C₃-C₆-branched alkyl chain;    -   C₃-C₆-branched alkenyl chain;    -   C₃-C₇-cycloalkyl;    -   CH₂—(C₃-C₇-cycloalkyl);    -   CH₂CF₃;    -   CH₂CH₂CF₃;    -   CH(CF₃)₂;-   the combination of X, D, and Q are selected from:    -   D=Q=N, and X=CH;    -   D=X=N, and Q=CH;    -   Q=X=N, and D=CH;    -   Q=N, and D=X=CH;-   V=NH;    -   O;    -   S;    -   CH₂;-   R₂ can be in any position on the ring and selected from:    -   phenyl;    -   substituted phenyl, wherein the substituents (1-2 in number) are        in any position and are independently selected from R₁, OR₁,        SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl, Br,        CF₃, C(O)R₁, C(O)NHR₁, phenyl, C(O)NHCHR₁CH₂OH;    -   1-naphthyl;    -   2-naphthyl;    -   heterocycles including:        -   2-pyridyl;        -   3-pyridyl;        -   4-pyridyl;        -   2-pyrimidyl;        -   4-pyrimidyl;        -   5-pyrimidyl;        -   thiophene-2-yl;        -   thiophene-3-yl;        -   2-furanyl;        -   3-furanyl;        -   oxazol-2-yl;        -   oxazol-4-yl;        -   oxazol-5-yl;        -   thiazol-2-yl;        -   thiazol-4-yl;        -   thiazol-5-yl;        -   imidazol-2-yl;        -   imidazol-4-yl;        -   pyrazol-3-yl;        -   pyrazol-4-yl;        -   isoxazol-3-yl;        -   isoxazol-4-yl;        -   isoxazol-5-yl;        -   isothiazol-3-yl;        -   isothiazol-4-yl;        -   isothiazol-5-yl;        -   1,3,4-thiadiazol-2-yl;        -   benzo[b]furan-2-yl;        -   benzo[b]thiophene-2-yl;        -   2-pyrrolyl;        -   3-pyrrolyl;        -   1,3,5-triazin-2-yl;        -   pyrazin-2-yl;        -   pyridazin-3-yl;        -   pyridazin-4-yl;        -   2-quinolinyl;        -   3-quinolinyl;        -   4-quinolinyl;        -   1-isoquinolinyl;        -   3-isoquinolinyl;        -   4-isoquinolinyl;    -   substituted heterocycle, wherein the substituents (1-2 in        number) are in any position and are independently selected from        Br, Cl, F, R₁, C(O)CH₃;-   R₃ are the same or different and independently selected from:    -   H;    -   C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph;    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;

R₄=H;

-   -   C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;

-   R₃ and R₄ can be linked together by a carbon chain to form a    5-8-membered saturated or unsaturated ring;

-   n₁=0-3;

-   n=0-3;

-   A=(CH₂);    -   (CH₂)₂;    -   (CH₂)₃;    -   (OCH₂CH₂);    -   (CHCH₃);

-   Y=H;    -   OR₁;    -   N(R₁)₂;    -   N(R₁)C(O)R₃;    -   N(R₁)C(O)R₅;    -   N(R₁)C(O)CH(R₆)NH₂;    -   N(R₁)SO₂R₃;    -   N(R₁)C(O)NHR₃;    -   N(R₁)C(O)OR₆;

-   R₅=C₃-C₇-cycloalkyl;

-   R₆=C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph;    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂.        Additional, general non-limiting syntheses of compounds of the        present invention of Formula XVI, Formula XVII and Formula XVIII        are shown below in General Flowsheet IV.

If in Formula X (Y=NH₂), then subsequent reaction of Formula X (Y=NH₂)with alkyl halide (R₈CH₂Z), an appropriate base, and a solvent; orreaction of Formula X (Y=NH₂) with aldehyde (R₈CHO) in the presence of asolvent and a suitable reducing agent provides purines of Formula XVIwherein Y=NHR₁, or N(R₁)₂. On the other hand, if in Formula X, Y alreadyis NHR₁, or N(R₁)₂, as a result of what Y started out as in Formula X,then this last step is unnecessary. If in Formula XVI (Y=NHR₁), thensubsequent reaction of Formula XVI (Y=NHR₁) with acid chloride (R₃COCl),or sulfonyl chloride (R₃SO₂Cl), or isocyanate (R₃NCO), or chloroformate(ClC(O)OR₆) reagents provides purines of Formula XX wherein Y=NR₁C(O)R₃,or NR₁C(O)R₅, or NR₁SO₂R₃, or NR₁C(O)NHR₃, or NR₁C(O)OR₆, respectively.On the other hand, if in Formula XVI, Y already is NR₁C(O)R₃, orNR₁C(O)R₅, or NR₁ SO₂R₃, or NR₁C(O)NHR₃, or NR₁C(O)OR₆, as a result ofwhat started out as in Formula XVI, then this last step is unnecessary.

If in Formula X (Y=NH₂), then subsequent reaction of Formula X (Y=NH₂)with acid (PNHCH(R₆)CO₂H), in a suitable solvent in the presence of anappropriate coupling agent provides a purine derivative; which uponsuitable deprotection provides purines of Formula XIX whereinY=NHC(O)CH(R₆)NH₂. On the other hand, if in Formula X, Y already isNHC(O)CH(R₆)NH₂, as a result of what Y started out as in Formula X, thenthis last step is unnecessary.

Definitions of the groups include:

-   Z=Br;    -   I;-   P=C(O)OtBu;    -   C(O)OCH₂Ph;    -   Fmoc;    -   Benzyl;    -   Alloc;-   R₁ are the same or different and independently selected from:    -   H;    -   C₁-C₆-straight chain alkyl;    -   C₂-C₆-straight alkenyl chain;    -   C₃-C₆-branched alkyl chain;    -   C₃-C₆-branched alkenyl chain;    -   C₃-C₇-cycloalkyl;    -   CH₂—(C₃-C₇-cycloalkyl);    -   CH₂CF₃;    -   CH₂CH₂CF₃;    -   CH(CF₃)₂;-   the combination of X, D, and Q are selected from:    -   D=Q=N, and X=CH;    -   D=X=N, and Q=CH;    -   Q=X=N, and D=CH;    -   Q=N, and D=X=CH;-   V=NH;    -   O;    -   S;    -   CH₂;-   R₂ can be in any position on the ring and selected from:    -   phenyl;    -   substituted phenyl, wherein the substituents (1-2 in number) are        in any position and are independently selected from R₁, OR₁,        SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl, Br,        CF₃, C(O)R₁, C(O)NHR₁, phenyl, C(O)NHCHR₁CH₂OH;    -   1-naphthyl;    -   2-naphthyl;    -   heterocycles including:        -   2-pyridyl;        -   3-pyridyl;        -   4-pyridyl;        -   2-pyrimidyl;        -   4-pyrimidyl;        -   5-pyrimidyl;        -   thiophene-2-yl;        -   thiophene-3-yl;        -   2-furanyl;        -   3-furanyl;        -   oxazol-2-yl;        -   oxazol-4-yl;        -   oxazol-5-yl;        -   thiazol-2-yl;        -   thiazol-4-yl;        -   thiazol-5-yl;        -   imidazol-2-yl;        -   imidazol-4-yl;        -   pyrazol-3-yl;        -   pyrazol-4-yl;        -   isoxazol-3-yl;        -   isoxazol-4-yl;        -   isoxazol-5-yl;        -   isothiazol-3-yl;        -   isothiazol-4-yl;        -   isothiazol-5-yl;        -   1,3,4-thiadiazol-2-yl;        -   benzo[b]furan-2-yl;        -   benzo[b]thiophene-2-yl;        -   2-pyrrolyl;        -   3-pyrrolyl;        -   1,3,5-triazin-2-yl;        -   pyrazin-2-yl;        -   pyridazin-3-yl;        -   pyridazin-4-yl;        -   2-quinolinyl;        -   3-quinolinyl;        -   4-quinolinyl;        -   1-isoquinolinyl;        -   3-isoquinolinyl;        -   4-isoquinolinyl;    -   substituted heterocycle, wherein the substituents (1-2 in        number) are in any position and are independently selected from        Br, Cl, F, R₁, C(O)CH₃;-   R₃ are the same or different and independently selected from:    -   H;    -   C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph;    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;-   R₄=H;    -   C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;-   R₃ and R₄ can be linked together by a carbon chain to form a    5-8-membered saturated or unsaturated ring;-   n₁=0-3;-   n=0-3;-   A=(CH₂);    -   (CH₂)₂;    -   (CH₂)₃;    -   (OCH₂CH₂);    -   (CHCH₃);-   Y=H;    -   OR₁;    -   N(R₁)₂;    -   N(R₁)C(O)R₃;    -   N(R₁)C(O)R₅;    -   N(R₁)C(O)CH(R₆)NH₂;    -   N(R₁)SO₂R₃;    -   N(R₁)C(O)NHR₃;    -   N(R₁)C(O)OR₆;-   R₅=C₃-C₇-cycloalkyl;-   R₆=C₁-C₄-straight chain alkyl;    -   C₃-C₄-branched chain alkyl;    -   C₂-C₄-alkenyl chain;    -   (CH₂)_(n)Ph;    -   (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents        are as defined above in R₂;-   R₈=C₁-C₅-straight chain alkyl;    -   C₂-C₅-straight alkenyl chain;    -   C₃-C₅-branched alkyl chain;    -   C₃-C₅-branched alkenyl chain;    -   C₃-C₇-cycloalkyl;    -   CF₃;    -   CH₂CF₃.        The synthesis of compound 5 is shown below in Scheme I.        The synthesis of compound 11 is shown below in Scheme II.        The syntheses of compounds 12, 13 and 14 are shown below in        Scheme III.        The synthesis of compound 17 is shown below in Scheme IV.        The synthesis of compound 17 is shown below in Scheme V.        The synthesis of compound 25 is shown below in Scheme VI.        The synthesis of compound 25 is shown below in Scheme VII.        The synthesis of compound 32 is shown below in Scheme VIII.        The syntheses of compounds 33 and 34 are shown below in Scheme        IX.        The syntheses of compounds 36, 38, and 40 are shown below in        Scheme X.        The synthesis of compound 43 is shown below in Scheme XI.        The synthesis of compound 46 is shown below in Scheme XII.        The synthesis of Compound 48 and 50 are shown below in Scheme        XIII.        The synthesis of Compound 53 is shown below in Scheme XIV.        The synthesis of compound 54 is shown below in Scheme XV.        The synthesis of compound 56 is shown below in Scheme XVI.        The synthesis of compound 58 is shown below in Scheme XVII.        The synthesis of compound 60 is shown below in Scheme XVIII.        The syntheses of compounds 61, and 62 are shown below in Scheme        XIX.        The syntheses of compounds 64, and 65 are shown below in Scheme        XX.        The syntheses of compounds 66, and 67 are shown below in Scheme        XXI.        The syntheses of compound 73 is shown below in Scheme XXII.        The synthesis of compounds 74, 75, and 76 are shown below in        Scheme XXIII.        The syntheses of compound 77 is shown below in Scheme XXIV.        The syntheses of compound 78 is shown below in Scheme XXV.        An alternative synthesis of compound 78, and the synthesis of        compound 79 are shown below in Scheme XXVI.        The synthesis of compound 80 is shown below in Scheme XXVII.        The syntheses of compounds 86, and 87 are shown below in Scheme        XXVIII.        The synthesis of compound 88 is shown below in Scheme XXIX.        The syntheses of compounds 93, and 94 are shown below in Scheme        XXX.        The syntheses of compounds 95, and 96 are shown below in Scheme        XXXI.        The synthesis of compound 97 is shown below in Scheme XXXII.        The syntheses of compounds 98, and 99 are shown below in Scheme        XXXIII.        The syntheses of compound 100 is shown below in Scheme XXXIV.        The syntheses of compounds 101, and 102 are shown below in        Scheme XXXV.        The syntheses of compounds 103, and 104 are shown below in        Scheme XXXVI.        The syntheses of compounds 106, 107, and 108 are shown below in        Scheme XXXVII.        The syntheses of compounds 109, and 110 are shown below in        Scheme XXXVIII.        The syntheses of compounds 111, and 112 are shown below in        Scheme XXXIX.        The synthesis of compound 113 is shown below in Scheme XL.        The syntheses of compounds 114, 115, 116, and 117 are shown        below in Scheme XLI.        The syntheses of compound 118 is shown below in Scheme XLII.        The syntheses of compounds 123 and 124 are shown below in Scheme        XLIII.        The syntheses of compounds 131 and 132 are shown below in Scheme        XLIV.        The syntheses of compounds 134 and 135 are shown below in Scheme        XLV.        The synthesis of compound 137 is shown below in Scheme XLVI.        The syntheses of compounds 139 and 140 are shown below in Scheme        XLVII.        The synthesis of compound 142 is shown below in Scheme XLVIII.        The synthesis of compound 144 is shown below in Scheme XLIX.        The synthesis of compound 146 is shown below in Scheme L.        The syntheses of compound 148 is shown below in Scheme LI.        The syntheses of compounds 149-152 are shown below in Scheme        LII.        The syntheses of compounds 153-156 are shown below in Scheme        LIII.        The syntheses of compounds 157-159 are shown below in Scheme        LIV.        The syntheses of compounds 160-163 are shown below in Scheme LV.        The syntheses of compounds 164-166 are shown below in Scheme        LVI.        The syntheses of compounds 167-168 are shown below in Scheme        LVII.        The syntheses of compounds 169-171 are shown below in Scheme        LVIII.        The syntheses of compounds 172-173 are shown below in Scheme        LIX.        The syntheses of compounds 174-176 are shown below in Scheme LX.        The syntheses of compounds 177-178 are shown below in Scheme        LXI.        The syntheses of compounds 179-180 are shown below in Scheme        LXII.        The syntheses of compounds 181-182 are shown below in Scheme        LXIII.        The syntheses of compounds 187-188 are shown below in Scheme        LXIV.        The syntheses of compounds 193 and 194 are shown below in Scheme        LXV.        The syntheses of compounds 199-200 are shown below in Scheme        LXVI.        The syntheses of compounds 205-206 are shown below in Scheme        LXVII.        The syntheses of compounds 207-210 are shown below in Scheme        LXVIII.        The syntheses of compounds 211-212 are shown below in Scheme        LXIX.        The synthesis of compounds 213-215 are shown below in Scheme        LXX.        The syntheses of compounds 216-217 are shown below in Scheme        LXXI.        The syntheses of compounds 218-219 are shown below in Scheme        LXXII.        The synthesis of compounds 221 is shown below in Scheme LXXIII.        The synthesis of compound 222 is shown below in Scheme LXXIV.        The synthesis of compound 223 is shown below in Scheme LXXV.        The synthesis of compound 224 is shown below in Scheme LXXVI.        The synthesis of compound 229 is shown below in Scheme LXXVII.        The syntheses of compounds 230-233 are shown below in Scheme        LXXVIII.        The syntheses of compounds 239-241 are shown below in Scheme        LXXIX.        The syntheses of compounds 242-243 are shown below in Scheme        LXXX.        The syntheses of compounds 248-250 are shown below in Scheme        LXXXI.        The syntheses of compounds 123 and 124 are shown below in Scheme        LXXXII.        The syntheses of compounds 258-260 are shown below in Scheme        LXXXIII.        The syntheses of compounds 261-263 are shown below in Scheme        LXXXIV.        The syntheses of compounds 264-265 are shown below in Scheme        LXXXV.        The synthesis of compound 266 is shown below in Scheme LXXXVI.

EXAMPLES

Proton NMR spectra were obtained on a Bruker AC 300 spectrometer at 300MHz or a Bruker 500 MHz spectrometer and were referenced totetramethylsilane as an internal standard. The IR spectrometer used wasa single beam Perkin-Elmer Spectrum 1000 FT-IR. All IR spectra obtainedwere prepared in a pressed disc of KBr. All IR spectra obtained wereacquired with a total of 4 accumulations at a resolution of 4.00 cm⁻¹.Melting points were obtained on a Mel-Temp II apparatus and areuncorrected. Mass spectra were obtained on either a Shimadzu QP-5000 ora PE Sciex API 150 Mass Spectrometer.

Example 1 Preparation of Compound 2

To the starting material 1 (1.0 g, 5.29 mmol) was added4-bromobenzylamine (2.53 g, 11.4 mmol), and EtOH (11 mL). The mixturewas stirred and heated at 50° C. in a round-bottomed flask and then H₂O(1 mL) and EtOH (10 mL) were added to dissolve the solids. The mixturewas refluxed for 1 h. Hünig's base (3.68 mL, 21.2 mmol) was added andrefluxed overnight, during which time a precipitate formed. The solutionwas filtered to provide a light yellow solid. The solid was dried invacuo (1.08 g, 60%): ¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (bs, 1H), 8.15 (s,1 H), 7.52 (d, 2H), 7.30 (d, 2H), 4.63 (bs, 2H); CI MS m/z=340[C₁₂H₉BrClN₅+H]⁺.

Example 2 Preparation of Compound 3

To the starting material 2 (1.08 g, 3.19 mmol) was added DMSO (11 mL),K₂CO₃ (2.20 g, 15.95 mmol), and 2-iodopropane (1 mL, 9.57 mmol). Thesolution was stirred overnight then poured into H₂O (75 mL) and stirred.Additional H₂O (25-50 mL) was added to the mixture to form a yellowsolid. The stirring was continued at 0° C. The solid was filtered invacuo. The crude product was purified by silica gel chromatography toprovide 3 (0.66 g, 50%) as a white solid: mp 136-140° C.; ¹H NMR (300MHz, CDCl₃) δ 7.78 (s, 1H), 7.49 (d, 2H), 7.28 (d, 2H), 6.12 (bs, 1H),4.90-4.70 (m, 3H), 1.61 (d, 6H).

Example 3 Preparation of Compound 4

To starting material 3 (1.44 g, 3.78 mmol) was added 2-amino-1-butanol(5.06 g, 56.7 mmol) and ethanol (5 mL) and the mixture was heated in asealed tube in an oil bath at 150-160° C. for 48 h. The cooled solutionwas transferred to a round-bottomed flask and the ethanol was removed invacuo. The crude product was purified by flash column chromatography onsilica gel to give 4 (0.90 g, 55%): ¹H NMR (300 MHz, CDCl₃) δ 7.44-7.41(m, 3H), 7.23 (d, 2H), 6.22 (s, 1H), 5.06 (s, 1H), 4.90 (d, 1H),4.78-4.68 (m, 2H), 4.65-4.55 (m, 1H), 3.91-3.80 (m, 2H), 3.66-3.60 (m,1H), 1.66-1.47 (m, 8H), 1.04-0.99 (t, 3H).

Example 4 Preparation of Compound 5

To starting material 4 (0.13 g, 0.29 mmol) was added3-acetamidophenylboronic acid (0.21 g, 1.19 mmol) and Pd(PPh₃)₄ (0.08 g,0.07 mmol), Na₂CO₃ (2M, 0.60 mL), and toluene (5 mL). The solution wasdegassed with argon for 10 min then heated at 130° C. for 6 h. Thecooled solution was diluted with water and then extracted with CH₂Cl₂(3×50 mL). The combined organic phases were washed with brine, driedover anhydrous Na₂SO₄, filtered, and concentrated to yield a viscousorange oil. The oil was purified by flash column chromatography onsilica gel and then the product crystallized upon standing to give 5(0.06 g, 41%) as a pale yellow solid: ¹H NMR (300 MHz, CDCl₃) δ8.01-7.21 (m, 9H), 6.48 (s, 1H), 4.97 (d, 1H), 4.82-4.70 (m, 2H),4.65-4.53 (m, 1H), 3.98-3.25 (m, 2H), 3.20-3.05 (m, 1H), 2.20 (s, 3H),1.69-1.45 (m, 8H), 1.07-0.98 (t, 3H).

Example 5 Preparation of Compound 7

To 4-iodobenzoic acid (52.2 g, 0.21 mol) was added CH₂Cl₂ (500 mL) andDMF (2 drops) at room temperature. Oxalyl chloride (32 g, 0.25 mol) wasadded dropwise in 0.5 h and stirred for 2 d. The volatiles were removedin vacuo to a volume of 150 mL to give the acid chloride and CH₂Cl₂. Toa mixture of ice (500 mL) and NH₄OH (29%; 100 mL) was added the CH₂Cl₂solution during 15 min. The resulting solids were collected, washed withCH₂Cl₂, and dried in vacuo. The solids were slurried in H₂O for 1 h. Thesolids were collected by filtration, washed in water and acetone, anddried in vacuo to give 7 (48 g; 92%): mp 213-216° C.

Example 6 Preparation of Compound 8

To a suspension of 7 (11 g, 45 mmol) in THF (50 mL) was added BH₃-THF(1M, 22.5 mL, 22.5 mmol). The resulting solution was heated under refluxovernight. The reaction was cooled in an ice bath and MeOH-HCl (60 mL)was slowly added dropwise. The resulting precipitate was filtered anddried to give 8 (10.8 g, 88%) as a white solid: mp 256-262° C. dec.; ¹HNMR (300 MHz, DMSO-d₆) δ 8.55 (bs, 3H), 7.79 (d, 2H), 7.32 (d, 2H), 3.98(s, 2H).

Example 7 Preparation of Compound 9

To compound 1 (7.63 g, 40.4 mmol) was added compound 8 (10.8 g, 40.4mmol), water (123 mL), and Hünig's base (14 mL, 81 mmol). The mixturewas heated to reflux for 5 h and stirred overnight at room temperatureto give a pale yellow solution. An additional quantity of water (150 mL)was added, refluxed for 3 h, then cooled overnight. A pale yellow solidwas formed which was filtered, washed with water, rinsed with EtOH (2×),and dried in vacuo to give yield 9 (13.3 g, 80%): ¹H NMR (300 MHz,DMSO-d₆) δ 8.68 (bs, 1H), 8.28 (s, 1H), 7.68 (d, 2H), 7.50 (d, 2H), 5.08(bs, 1H), 4.50 (d, 2H).

Example 8 Preparation of Compound 10

To compound 9 (12.2 g, 31.7 mmol) was added K₂CO₃ (35 g, 0.25 mol),2-iodopropane (13 g, 0.13 mol) and DMSO (210 mL). The reaction mixturewas stirred under N₂ at room temperature overnight, then poured into H₂O(1.5 L) and stirred for 2 d. The precipitate was collected as anoff-white solid and washed with Et₂O. The aqueous layer was extractedwith EtOAc (2×) and the combined organic phases were washed with brine,dried over Na₂SO₄, filtered, and evaporated to give an off-white foam(6.4 g). This off-white foam was combined with the precipitate andwashed with Et₂O to give 10 (11.0 g): ¹H NMR (300 MHz, DMSO-d₆) δ 8.91(m, 1H), 8.38 (s, 1H), 7.74 (d, 2H), 7.21 (d, 2H), 5.11 (bs, 1H), 4.68(m, 1H), 4.60 (d, 2H), 1.48 (d, 6H).

Example 9 Preparation of Compound 11

Compound 10 (1.52 g, 3.55 mmol), trans-1,4-diaminocyclohexane (6.35 g,55.60 mmol), and EtOH (18 mL) were placed in a sealed tube. The reactionmixture was heated at 120-190° C. for 24 h. The reaction was thenallowed to cool to room temperature. The reaction mixture was filteredand the filtrate evaporated. The residue was purified by columnchromatography, and dried in vacuo for 16 h to yield 11 (1.60 g, 89%) asa yellow sticky oil: ¹H NMR (300 MHz, CDCl₃) δ 7.62 (d, 2H), 7.44 (s,1H), 7.08 (d, 2H), 6.14 (br, 1H), 4.75-4.63 (m, 2H), 4.63-4.54 (m, 2H),3.75-3.63 (m, 1H), 2.72-2.57 (m, 2H), 2.18-2.00 (m, 2H), 2.00-1.75 (m,4H), 1.54 (d, 6H), 1.39-1.00 (m, 3H); API MS m/z=506 [C₂₁H₂₈IN₇+H]⁺.

Example 10 Preparation of Compound 12

To compound 11 (0.133 g, 0.26 mmol) was added DME (2.5 mL) and3-thiopheneboronic acid (0.12 g, 0.97 mmol) in a round-bottomed flaskand equipped with a condenser purged with argon. To this was added DME(3 mL) followed by tris(dibenzylidoneacetone)dipalladium (0.01 g, 0.01mmol) and PPh₃ (0.04 g, 0.15 mmol). Na₂CO₃ (2M, 0.6 mL) and DME (1 mL)was added to the reaction mixture and the reaction mixture was allowedto reflux for 18.5 h, then stirred at room temperature under argon for46 h. The reaction mixture was diluted with H₂O and extracted withCH₂Cl₂. The combined organic phases were washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by column chromatography to yield 12 (0.050 g, 41%) as a tansolid: ¹H NMR (300 MHz, CDCl₃) δ 7.56-7.50 (m, 4H), 7.44-7.35 (m, 3H),6.02 (br, 1H), 4.78 (d, 2H), 4.69-4.54 (m, 2H), 3.75 (br, 1H), 2.69 (br,1H), 2.15 (br, 2H), 1.88 (br, 3H), 1.54 (d, 7H), 1.33-0.97 (m, 4H); APIMS m/z=462 [C₂₅H₃₁N₇S+H]⁺.

Example 11 Preparation of Compound 13

DME (3 mL), tris(dibenzylidoneacetone)dipalladium (0.01 g, 0.01 mmol),and PPh₃ (0.04 g, 0.15 mmol) were placed in a round-bottomed flaskfitted with a condenser and maintained under argon. Compound 11 (0.13 g,0.26 mmol), and 4-methylbenzeneboronic acid (0.13 g, 0.98 mmol)dissolved in Na₂CO₃ (2M, 0.6 mL) and DME (1 mL) were added to thereaction mixture. The reaction mixture was refluxed for 19.5 h andstirred at room temperature for 4 h. The reaction mixture was dilutedwith water and extracted with CH₂Cl₂. The combined organic phases werewashed with brine, dried over anhydrous Na₂SO₄, and evaporated. Thecrude product was purified by column chromatography and dried in vacuofor 22 h to yield the desired product 13 (54 mg, 44%) as an off-whitesolid: ¹H NMR (300 MHz, CDCl₃) δ 7.56-7.41 (m, 7H), 7.23 (s, 1H), 5.92(br, 1H), 4.83 (d, 2H), 4.74-4.58 (m, 2H), 3.77 (br, 1H), 2.70 (br, 1H),2.40 (s, 3H), 2.16 (d, 3H), 1.88 (d, 3H), 1.55 (d, 7H), 1.33-0.97 (m,4H); API MS m/z=470 [C₂₈H₃₅N₇+H]⁺.

Example 12 Preparation of Compound 14

DME (3 mL), tris(dibenzylideneacetone)dipalladium (0.01 g, 0.01 mmol),and PPh₃ (0.04 g, 0.15 mmol) were placed in a round-bottomed flask witha condenser under argon. Compound 11 (0.13 g, 0.25 mmol) and3-chloro-4-fluoroboronic acid (0.15 g, 0.88 mmol) were dissolved inNa₂CO₃ (2M, 0.6 mL) and DME (1 mL) were added to the reaction mixture,refluxed for 19 h then stirred at room temperature for 2 h. The reactionmixture was diluted with water and extracted with CH₂Cl₂. The combinedorganic phases were washed with brine, dried over anhydrous Na₂SO₄, andevaporated. The crude product was purified by repeated columnchromatography to yield 14 (0.019 g, 15%): ¹H NMR (300 MHz, CDCl₃) δ7.59-7.53 (m, 1H), 7.47-7.35 (m, 4H), 7.26-7.14 (m, 3H), 5.81 (br, 1H),4.81 (d, 2H), 4.72-4.54 (m, 2H), 3.72 (br, 1H), 2.69 (br, 1H), 2.21-2.03(m, 3H), 1.94-1.78 (m, 3H), 1.54 (d, 6H), 1.33-1.12 (m, 4H); API MSm/z=508 [C₂₇H₃₁ClFN₇+H]⁺.

Example 13 Preparation of Compound 16

A solution of 15 (2.5 g, 15.8 mmol) and ether was cooled to −78° C. In aseparate flask, n-BuLi (15.8 mmol) was also cooled to −78° C. Thesolution of 15 was added to the n-BuLi solution via cannula to give adark red solution. The reaction mixture was stirred for 5 min prior tothe rapid addition of (n-Bu)₃SnCl (6.2 g, 19 mmol). The resulting brightyellow solution was stirred at −78° C. for 2 h, allowed to warm to roomtemperature, and stirred for another 10 min. The solution was thendiluted with H₂O (80 mL) and extracted with ethyl acetate (3×50 mL). Theorganic extracts were combined, washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo to yield the crude product as ayellow oil. Purification by column chromatography gave the product 16(4.89 g, 84%) as a pale yellow liquid: ¹H NMR (300 MHz, CDCl₃) δ 8.72(d, 1H), 7.48-7.46 (m, 1H), 7.40-7.38 (m, 1H), 7.11-7.09 (m, 1H),1.61-1.50 (m, 6H), 1.38-1.26 (m, 6H), 1.14-1.09 (m, 6H), 0.97-0.77 (t,9H).

Example 14 Preparation of Compound 17

To compound 16 (0.18 g, 0.48 mmol) was added compound 4 (0.14 g, 0.33mmol), Pd(PPh₃)₄ (0.05 g, 0.49 mmol), and toluene (10 mL) in a sealedtube under an argon atmosphere. The solution was degassed with argon andheated at 135° C. in an oil bath for 3 h. The solution was cooled toroom temperature, diluted with saturated NaHCO₃, and extracted withCH₂Cl₂ (3×30 mL). The organic layer was washed with brine, dried overNa₂SO₄, and concentrated in vacuo to give a light brown oil. The residuewas purified by flash column chromatography using MeOH/CH₂Cl₂ (10%) toafford 17 as a white solid. The sample was dissolved intohexane/CH₂Cl₂/MeOH and then precipitated with diethyl ether, filtered,and rinsed several times with ether to provide in 17 (30.3 mg): mp95-100° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.68 (d, 1H), 7.96 (d, 2H),7.77-7.69 (m, 2H), 7.49-7.45 (m, 3H), 7.24-7.20 (m, 1H), 5.99 (s, 1H),5.11 (s, 1H), 4.88-4.83 (m, 3H), 4.65-4.56 (m, 1H), 3.91-3.80 (m, 2H),3.65-3.60 (m, 1H), 1.66-1.52 (m, 8H), 1.05-0.99 (t, 3H); IR (KBr) 3411,2968, 1601, 1489 cm⁻¹; CI MS m/z=432 [C₂₄H₂₉N₇+H]⁺.

Example 15 Preparation of Compound 19

To a solution of n-BuLi (2.5M hexane solution, 10.9 mL, 27.4 mmol) inethyl ether 28 mL at −78° C. was added 2-bromopyridine (4.33 g, 27.4mmol) in ethyl ether (15 mL). After stirring for 30 min, a solution oftrimethylstannylchloride (6.0 g, 30 mmol) in THF (10 mL) was added.Stirring was continued at −78° C. for 2 h and the mixture was thenwarmed up to room temperature and filtered. The precipitate was washedwith ether and the combined the ether filtrates were concentrated togive the crude product: ¹H NMR (500 Hz, CDCl₃) δ 8.69-8.68 (d, 1H),7.47-7.07 (m, 3H), 0.30 (s, 9H).

Example 16 Preparation of Compound 21

A mixture of 4-bromobenzonitrile (1.68 g, 9.2 mmol), crude2-trimethylstannylpyridine (3.33 g, 13.8 mmol), and PdCl₂(PPh₃)₂ (321mg, 0.46 mmol) in DMF (25 mL) was heated at 150-155° C. in pressure tubefor 24 h. The DMF was distilled off under reduced pressure and theresidue was filtered through a short column of basic alumina and washedwith ethyl acetate and then concentrated. Flash chromatography of theresidue on silica gel gave the product (41%) as a white solid: mp99-100° C.; ¹H NMR (500 Hz, CDCl₃) δ 8.74 (dd, J₁=1 Hz, J₂=1.7 Hz, 1H),8.12 (d, J=8.6 Hz, 2H), 7.83-7.76 (m, 4H), 7.32 (m, 1H).

Example 17 Preparation of Compound 22

To LiAlH₄ (8 mmol) in THF (25 mL) was added 21 (0.96 g, 5.3 mmol) in THF(15 mL) slowly while the flask was cooled with ice. The mixture wasstirred at room temperature for 10-30 min then stirred at reflux for 4 hunder nitrogen. The mixture was cooled in an ice bath and aqueous sodiumhydroxide solution (0.5 mL, 10%) was added. The mixture was stirreduntil the residue became white and the solid was filtered and washedwith methylene chloride (4×5 mL). The methylene chloride solution wasdried with anhydrous sodium sulfate, concentrated, and the crude productwas chromatographed on silica gel to give the product as a yellowliquid. A small amount of ethanol was added and the pure amine 22 wasobtained as a white solid (74%) after filtration: mp 114-117° C.; ¹H NMR(500 Hz, CDCl₃) δ 8.66 (d, J=4.4 Hz, 1H), 7.94 (d, J=8.1 Hz, 2H), 7.70(m, 2H), 7.39 (d, J=8.0 Hz), 7.19 (m, 1H), 3.90 (s, 2H), 1.98 (s, 2H).

Example 18 Preparation of Compound 23

A mixture of 2,6-dichloropurine (1, 0.19 g, 1 mmol), amine 22 (0.39 g,2.15 mmol) in ethanol (13 mL), and water (3.4 mL) was heated at 100-110°C. under nitrogen for 24 h and then it was cooled to room temperature.The mixture was concentrated and water (5 mL) was added. A solid wasfiltered and washed with water (2×5 mL) and dried under vacuum to givethe product (93%) as yellow solid: mp 260° C. (dec); ¹H NMR (500 Hz,DMSO-d₆) δ 12.4 (bs, 1H), 8.76 (m, J=1 Hz, 1H), 8.28 (s, 1H), 8.16 (d,J=8.1 Hz, 2H), 8.03 (d, J=7.8 Hz, 1H), 7.97 (m, 1H), 7.58 (d=8.6 Hz,2H), 7.45 (m, 1H), 4.82 (s, 2H).

Example 19 Preparation of Compound 24

To the solution of compound 23 (0.33 g, 1 mmol) in DMSO (5.2 mL), addedpotassium carbonate (0.7 g, 5 mmol) and 2-iodopropane (0.5 g, 3 mmol).The mixture was stirred at ambient temperature under nitrogen for 24 hand poured into ice water (30 mL). After filtration, the solid waswashed with water (4×5 mL), dried under vacuum to give the crude productas a yellow solid. Flash column chromatography of the crude product onsilica gel and recrystallization provided the pure product (76%) aswhite crystals: mp 178-179° C.; ¹H NMR (500 Hz, CDCl₃) δ 8.68 (m, 1H),7.96 (d, J=8 Hz, 2H), 7.76-7.70 (m, 2H), 7.73 (s, 1H), 7.47 (d, J=8 Hz,2H), 7.22 (m, 1H), 4.89 (s, 1H), 4.79 (m, 1H), 1.54 (d, J=6.8 Hz, 6H);CI MS m/z=379 [C₂₀H₁₉ClN₆+H]⁺. Anal. Calcd. for C₂₀H₁₉ClN₆: C, 63.41; H,5.05; N, 22.18. Found: C, 63.07; H, 5.01; N, 22.01.

Example 20 Preparation of Compound 17

To compound 24 (0.7 g, 1.8 mmol) was added (R)-(−)-2 amino-1-butanol(3.5 g, 3.9 mmol) stirred in a sealed tube for 2 h at 190° C. Thereaction mixture was allowed to cool and then was partitioned betweenEtOAc and brine. The EtOAc was separated, washed with saturated brine(4×), dried with Na₂SO₄, and concentrated. The product was air dried togive an oil, then dissolved in EtOAc. The EtOAc solution was cooledagain, and the precipitate collected, washed with cold EtOAc (2×), airdried, and heated in vacuo for 2 h to give 17 (0.54 g, 67%): mp 98-100°C.; ¹H NMR (300 MHz, CDCl₃) δ 8.00-7.85 (m, 2H), 7.75-7.55 (m, 2H),7.50-7.35 (m, 3H), 7.30-7.15 (m, 1H), 6.40-6.20 (bs, 1H), 5.00-4.82 (m,1H), 4.80-4.68 (bs, 3H), 4.60 (heptuplet, 1H), 3.98-3.70 (m, 2H),3.70-3.54 (dd, 1H), 2.10 (bs, 1H), 1.75-1.53 (m, 2H), 1.51 (d, 6H), 1.00(t, 3H); IR (KBr) 3406, 2969, 1601, 1490, 1389, 1254, 779 cm⁻¹; API MSm/z=432 [C₂₄H₂₉N₇O+H]⁺.

Example 21 Preparation of Compound 25

To compound 4 (0.14 g, 0.33 mmol) was added 3-(tributylstannyl)pyridine(0.15 g, 0.33 mmol), Pd(PPh₃)₄ (0.06 g, 0.41 mmol), and toluene (10 mL).The solution was degassed with argon for 8 min in a sealed tube, andheated in an oil bath for 3 h at 130° C. The cooled reaction mixture wasdiluted with saturated NaHCO₃ and extracted with CH₂Cl₂ (3×50 mL). Thecombined organic extracts were washed with brine and dried over Na₂SO₄.The reaction mixture was purified by column chromatography on silica gelto give the desired coupling product. The product was dissolved inacetonitrile and washed with hexane (3×10 mL) to remove a portion of thetin contaminants. The reaction mixture was again purified by columnchromatography on reversed phase silica gel to give compound 25 (0.04g): ¹H NMR (300 MHz, CDCl₃) δ 8.83 (s, 1H), 8.58 (d, 1H), 7.88-7.83 (m,1H), 7.56-7.46 (m, 5H), 7.38-7.33 (m, 1H), 5.99 (s, 1H), 5.11 (s, 1H),4.90-4.83 (m, 2H), 4.63-4.56 (m, 1H), 3.92-3.81 (m, 2H), 3.67-3.60 (m,1H), 1.69-1.49 (m, 8H), 1.05-1.00 (t, 3H); CI MS m/z=432 [C₂₄H₂₉N₇O+H]⁺.

Example 22 Preparation of Compound 27

A mixture of diethyl(3-pyridyl)borane (26, 540 mg, 3.67 mmol),4-bromobenzonitrile (803 mg, 4.41 mmol) and Pd(PPh₃)₄ (144 mg, 0.13mmol) in toluene (9 mL), ethanol (1.3 mL) and 2M aqueous sodiumcarbonate solution (4.1 mL, 8.2 mmol) was heated at 90-100° C. undernitrogen for 27 h. The mixture was cooled to room temperature and water(10 mL) was added. The organic layer was separated and the aqueous layerwas extracted with ethyl acetate (2×20 mL). The combined organic layerswere washed with brine (2×15 mL) and dried over anhydrous sodiumsulfate. Flash chromatography of the crude product on silica gave theproduct as a white solid (80%): mp 95-96° C.

Example 23 An Alternative Preparation of 27 is Described Below

A flask charged with 4-bromobenzonitrile (360 mg, 2.0 mmol),bis(pinacolato)diboron (560 mg, 2.2 mmol), potassium acetate (590 mg,6.0 mmol) and PdCl₂(dppf) (49 mg, 0.06 mmol) was flushed with nitrogenand DMF (12 mL) was added. The mixture was heated at 80-85° C. for 4 hand then cooled to room temperature at which time PdCl₂(dppf) (49 mg,0.06 mmol), 3-bromopyridine (385 δL, 3.40 mmol), and 2M aqueous sodiumcarbonate solution (5 mL, 10 mmol) was added. The mixture was stirred at80-85° C. for 24 h and extracted with ethyl ether (3×30 mL) and thenwashed with brine (3×15 mL) and dried with anhydrous sodium sulfate.Flash chromatography of the crude product on silica gel gave the productas white crystals (56%): mp 96-97° C.; ¹H NMR (500 Hz, CDCl₃) δ 8.55(dd, J₁=1 Hz, J₂=1.4 Hz, 1H), 8.66 (m, 1H), 7.90-7.87 (m, 1H), 7.77 (d,J=7.8 Hz, 2H), 7.69 (d, J=8.8 Hz, 2H), 7.42 (m, 1H).

Example 24 Preparation of Compound 28

To LiAlH₄ (8 mmol) in THF (25 mL) was added 27 (0.96 g, 5.3 mmol) in THF(25 mL) slowly while the flask was cooled with ice. The mixture wasstirred at room temperature for 10-30 min then stirred at reflux for 4 hunder nitrogen. The mixture was cooled in an ice bath and aqueous sodiumhydroxide solution (0.5 mL, 10%) was added. The mixture was stirreduntil the residue became white and the solid was filtered and washedwith methylene chloride (4×5 mL). The methylene chloride solution wasdried with anhydrous sodium sulfate, concentrated, and the crude productwas chromatographed on silica gel to give the product as a yellowliquid. A small amount of ethanol was added and the pure amine 28 wasobtained as a white solid (46%) after filtration: mp 94-96° C.; ¹H NMR(500 Hz, CDCl₃) δ 8.74 (d, J=2.4 Hz, 1H), 8.48 (dd, J₁=1.5 Hz, J₂=4.7Hz, 1H), 7.77 (m, 1H), 7.45 (d, J=8.10 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H),7.25 (m, 1H), 3.83 (s, 2H), 2.25 (s, 2H).

Example 25 Preparation of Compound 29

A mixture of 2,6-dichloropurine (1, 0.19 g, 1 mmol), amine 28 (0.4 g,2.15 mmol) in ethanol (13 mL), water (3 mL) was heated at 100-110° C.under nitrogen for 24 h and then it was cooled to room temperature. Themixture was concentrated and water (5 mL) was added. A solid wasfiltered and washed with water (2×5 mL) and dried under vacuum to givethe product (92%) as a yellow solid: mp 219° C. (dec); ¹H NMR (500 Hz,DMSO-d₆) δ 13.2 (bs, 1H), 8.99 (s, 1H), 8.66 (d, J=3.5 Hz, 1H), 8.28 (s,1H), 8.16 (d, J=7.3 Hz, 1H), 7.80 (d, J=7.6 Hz, 2H), 7.60-7.57 (m, 3H).

Example 26 Preparation of Compound 30

To a solution of 29 (0.3 g, 1 mmol) in DMSO (5 mL), was added potassiumcarbonate (0.7 g, 5 mmol) and 2-iodopropane (0.5 g, 3 mmol). The mixturewas stirred at ambient temperature under nitrogen for 24 h and pouredinto ice water (30 mL). After filtration, the solid was washed withwater (4×5 mL), dried under vacuum to give the crude product as a yellowsolid. Flash column chromatography of the crude product on silica geland recrystallization provided the pure product (76%) as white crystals:mp 178-179° C.; ¹H NMR (500 Hz, CDCl₃) δ 8.82 (d, J=1.3 Hz, 1H),8.59-8.58 (m, 1H), 7.86-7.84 (m, 1H), 7.72 (s, 1H), 7.56-7.48 (m, 4H),7.37-7.34 (m, 1H), 4.88 (s, 2H), 4.82 (m, 1H), 1.56 (d, J=0.7 Hz, 3H),1.55 (d, J=0.8 Hz, 3H); CI MS m/z=379 [C₂₀H₁₉ClN₆+H]⁺. Anal. Calcd. forC₂₀H₁₉ClN₆: C, 63.41; H, 5.05; N, 22.18. Found: C, 63.24; H, 4.97; N,21.93.

Example 27 Preparation of Compound 32

To a mixture of 4 (0.05 g, 0.11 mmol) was added4-(tributylstannyl)pyridine (0.06 g, 0.16 mmol), Pd(PPh₃)₄ (0.02 g, 0.02mmol), and toluene (2.5 mL). The reaction mixture was degassed andheated in a sealed tube at 125° C. for 3 h. The reaction mixture wascooled to room temperature then saturated NaHCO₃ (30 mL) was addedfollowed by extraction with CH₂Cl₂ (3×30). The organic layer was washedwith brine (50 mL), dried with MgSO₄, and concentrated. The reactionmixture was purified by column chromatography on silica gel to give 32:¹H NMR (300 MHz, CDCl₃) δ 8.65 (s, 2H), 7.60-7.57 (m, 2H), 7.49-7.45 (m,5H), 6.20 (s, 1H), 4.93 (d, 1H), 4.84 (s, 2H), 4.65-4.57 (m, 1H),3.92-3.80 (m, 2H), 3.68-3.51 (m, 1H), 1.68-1.58 (m, 2H), 1.52 (d, 6H),1.05-0.99 (t, 3H).

Example 28 Preparation of Compound 33

To compound 4 (0.18 g, 0.43 mmol) was added 4-vinylphenylboronic acid(0.19 g, 1.28 mmol), Pd(PPh₃)₄ (0.09 g, 0.08 mmol), Na₂CO₃ (2M, 0.85mL), was added toluene (5 mL). The mixture was degassed with argon for10 min. The resulting solution was heated in a sealed tube at 135° C.for 4.5 h. The cooled solution was diluted with water and extracted withCH₂Cl₂ (3×50 mL). The combined organic extracts were washed with brineand dried over Na₂SO₄. The solution was purified by flash columnchromatography (2×) on silica gel to give the desired product 33 as ayellow solid (0.09 g): mp 130-131° C.; ¹H NMR (300 MHz, CDCl₃) δ7.57-7.42 (m, 9H), 6.80-6.70 (dd, 1H), 5.98 (s, 1H), 5.79 (d, 1H), 5.27(d, 1H), 4.88 (d, 1H), 4.84-4.72 (m, 2H), 4.63-4.56 (m, 1H), 3.92-3.81(m, 2H), 3.66-3.60 (m, 1H), 1.68-1.52 (m, 8H), 1.05-1.00 (t, 3H); IR(CH₂Cl₂) 3293, 2968, 1601, 1489, 1390 cm⁻¹; CI MS m/z=457[C₂₇H₃₂N₆O+H]⁺.

Example 29 Preparation of Compound 34

To compound 33 (0.008 g, 0.016 mmol) was added OsO₄ (0.007 g, 0.026mmol), pyridine (0.08 mL), and toluene (0.75 mL). The reaction mixturewas stirred at room temperature in the dark for 1 h, concentrated invacuo, and then slurried in methanol/water (9:1). Sodium metabisulfite(0.07 g) was added and the reaction was stirred for 1 h. The mixture waswashed with brine, extracted with CH₂Cl₂ (3×10 mL), dried over Na₂SO₄,and concentrated. The product was purified by column chromatography onsilica gel to give compound 34 (0.003 g) as a tan solid: ¹H NMR (300MHz, CDCl₃) δ 7.51 (s, 1H), 7.43-7.35 (m, 6H), 7.25-7.22 (m, 2H), 6.51(s, 1H), 4.98 (d, 1H), 4.35-4.25 (m, 2H), 4.64-4.54 (m, 1H), 3.93-3.80(m, 3H), 3.74-3.59 (m, 3H), 1.68-1.58 (m, 2H), 1.52 (d, 6H), 1.06-0.99(t, 3H).

Example 30 Preparation of Compound 36

To compound 4 (0.12 g, 0.27 mmol) was added 3-aminophenylboronic acidhydrochloride (0.12 g, 0.69 mmol), and Pd(PPh₃)₄ (0.09 g, 0.75 mmol) ina sealed tube filled with argon. To this mixture was added toluene (5mL) and Na₂CO₃ (2M, 0.55 mL). The resulting solution was degassed withargon for 5 min and placed in a 130° C. oil bath for 6 h. The cooledsolution was diluted with water and extracted with CH₂Cl₂ (3×50 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated. The solution was purified by column chromatography onsilica gel to yield 36 (0.04 g, 36%): ¹H NMR (300 MHz, CDCl₃) δ7.52-7.46 (m, 3H), 7.39 (d, 2H), 7.23-7.18 (m, 1H), 6.96 (d, 1H), 6.88(t, 1H), 6.68-6.66 (m, 1H), 6.12 (s, 1H), 4.90 (d, 1H), 4.79 (s, 2H),4.62-4.57 (m, 1H), 3.92-3.76 (m, 4H), 3.66-3.60 (m, 1H), 1.65-1.48 (m,8H), 1.04-0.99 (t, 3H); CI MS m/z=446 [C₂₅H₃₁N₇O+H]⁺.

Example 31 Preparation of Compound 38

To a suspension of Pd(PPh₃)₄ (0.02 g, 0.01 mmol) in anhydrous DME (8 mL)was added 4 (0.12 g, 0.27 mmol) and the mixture stirred at roomtemperature for 10 min. To this solution was added3-(trifluoromethyl)phenylboronic acid (37; 0.12 g, 0.65 mmol) in aminimum of EtOH, followed by Na₂CO₃ (2M, 0.27 mL), and the resultingmixture was heated at reflux for 20 h. The cooled reaction mixture wasdiluted with water and extracted with CH₂Cl₂ (3×50 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated. The reaction mixture was purified by column chromatographyon normal phase silica gel followed by reversed phase columnchromatography to obtain 38 (0.04 g, 33%) as an off white solid: mp60-67° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.81 (s, 1H), 7.74 (d, 1H),7.58-7.45 (m, 7H), 5.98 (s, 1H), 4.90-4.83 (m, 3H), 4.63-4.59 (m, 1H),3.90-3.81 (m, 2H), 3.66-3.60 (m, 1H), 1.68-1.51 (m, 8H), 1.05-1.00 (t,3H); IR (KBr) 3406, 2969, 1602, 1489, 1335 cm⁻¹; CI MS m/z=499[C₂₆H₂₉FN₇O+H]⁺.

Example 32 Preparation of Compound 40

A mixture of 4 (0.13 g, 0.31 mmol), 2-naphthaleneboronic acid (39; 0.11g, 0.62 mmol) and Pd(PPh₃)₄ (0.09 g, 0.08 mmol) was placed in a sealedtube that was filled with argon. To the mixture was added toluene (5 mL)and Na₂CO₃ (2M, 0.62 mL). The tube was quickly sealed and heated at 125°C. in an oil bath for 6 h. The cooled solution was diluted with waterand extracted with CH₂Cl₂ (3×50 mL). The organic layers were washed withbrine, dried over Na₂SO₄, and concentrated. The reaction mixture waspurified by column chromatography on normal phase silica gel, followedby reversed phase chromatography to give 40 (0.04 g, 28%): mp 70-75° C.;¹H NMR (300 MHz, CDCl₃) δ 8.02 (s, 1H), 7.92-7.84 (m, 3H), 7.74-7.67 (m,3H), 7.51-7.44 (m, 5H), 5.96 (s, 1H), 4.89-4.84 (m, 3H), 4.66-4.57 (m,1H), 3.93-3.82 (m, 2H), 3.67-3.61 (m, 1H), 1.76-1.50 (m, 8H), 1.06-1.01(t, 3H); IR (KBr) 3422, 2927, 1601, 1491, 1388 cm⁻¹.

Example 33 Preparation of Compound 43

To compound 4 (0.14 g, 0.33 mmol) was added 4-methoxyphenylboronic acid(42, 0.11 g, 0.71 mmol), Pd(PPh₃)₄ (0.10 g, 0.087 mmol), Na₂CO₃ (2M,0.66 mL), and toluene (7 mL). The solution was degassed for 8 min withargon and heated in an oil bath at 125° C. for 6 h. The cooled solutionwas diluted with water and extracted with CH₂Cl₂ (3×50 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The reaction mixture was purified by normal phase columnchromatography followed by reversed phase chromatography to give 43(0.05 g, 28%) as a white solid: mp 128-130° C.; ¹H NMR (300 MHz, CDCl₃)δ 7.52-7.50 (m, 5H), 7.41 (d, 2H), 6.97 (d, 2H), 5.93 (s, 1H), 4.89-4.79(m, 3H), 4.63-4.56 (m, 1H), 3.92-3.81 (m, 5H), 3.67-3.60 (m, 1H),1.68-1.49 (m, 8H), 1.05-1.00 (t, 3H); IR (KBr) 3417, 2931, 1610, 1499,1389 cm⁻¹; CI MS m/z=461 [C₂₆H₃₂N₆O₂+H]⁺.

Example 34 Preparation of Compound 45

To a solution of s-BuLi (5 mL, 6.24 mmol) and TMEDA (1 mL) in anhydrousTHF (35 mL) at −75° C. under argon was added dropwise a solution ofN,N-diethylbenzamide (0.98 g, 5.57 mmol) in THF (5 mL). The mixture wasstirred for 50 min and then treated with trimethylborate (2 mL, 17mmol). The solution was allowed to warm to room temperature overnight.The colorless solution was cooled to 0° C. and acidified to pH=6 with 2NHCl. The THF was removed in vacuo and the residue was diluted withwater. This was extracted with CH₂Cl₂ (3×50 mL) and the combined organiclayers were washed with brine, dried over Na₂SO₄, concentrated in vacuo,followed by removal of trace solvent on the vacuum pump to give 45 as anoff-white foamy solid: ¹H NMR (300 MHz, CD₃OD) δ 7.67-7.39 (m, 4H),3.88-3.69 (q, 4H), 1.41-1.30 (t, 6H).

Example 35 Preparation of Compound 46

To compound 4 (0.14 g, 0.31 mmol) was added2-(diethylcarbamoyl)phenylboronic acid (45, 0.29 g, 1.31 mmol),Pd(PPh₃)₄ (0.1 g, 0.09 mmol), Na₂CO₃ (2M, 0.63 mL), toluene (5 mL), andthe mixture degassed with argon for 10 min. The mixture was heated in anoil bath for 5 h at 135° C. The cooled solution was diluted with waterand extracted with CH₂Cl₂ (3×50 mL). The organic layers were combined,washed with brine, dried over Na₂CO₃, and concentrated. The reactionmixture was purified by normal phase column chromatography on silicagel, followed by reversed phase chromatography to give 46 (0.03 g, 18%)as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 7.49-7.36 (m, 9H), 6.18 (s,1H), 4.93 (d, 1H), 4.78 (s, 2H), 4.64-4.55 (m, 1H), 3.92-3.60 (m, 4H),3.06-2.92 (m, 2H), 2.69-2.64 (m, 1H), 1.68-1.51 (m, 8H), 1.04-0.99 (t,3H), 0.91-0.86 (t, 3H), 0.77-0.72 (t, 3H); CI MS m/z=530[C₃₀H₃₉N₇O₂+H]⁺.

Example 36 Preparation of Compound 48

To a suspension of Pd(PPh₃)₄ (0.08 g, 0.69 mmol) in DME was added 4(0.129 g, 0.30 mmol) and the mixture stirred for 10 min at roomtemperature. To this was added 3-nitrophenylboronic acid (47, 0.157 g,0.94 mmol) and Na₂CO₃ (2 M, 0.59 mL). The solution was heated at refluxunder argon overnight. The cooled solution was diluted with water andextracted with CH₂Cl₂ (3×50 mL). The organic layers were combined,washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thesolution was purified by flash column chromatography on silica gel togive 48 (0.04 g, 29%) as a bright yellow solid: mp 73-77° C.; ¹H NMR(300 MHz, CDCl₃) δ 8.43 (s, 1H), 8.20 (d, 1H), 7.89 (d, 1H), 7.63-7.43(m, 6H), 6.01 (s, 1H), 4.95-4.76 (m, 3H), 4.68-4.58 (m, 1H), 3.98-3.80(m, 2H), 3.68-3.60 (m, 1H), 1.71-1.40 (m, 8H), 1.02-0.98 (t, 3H); IR(KBr) 3405, 2930, 1713, 1602, 1490, 1351 cm⁻¹; CI MS m/z=476[C₂₅H₂₉N₇O₃+H]⁺.

Example 37 Preparation of Compound 50

To a suspension of Pd(PPh₃)₄ (0.09 g, 0.08 mmol) in DME (5 mL) was added4 (0.14 g, 0.32 mmol) and the mixture stirred at room temperature for 15min. To this was added benzo[b]furan-2-boronic acid (49, 0.153 g, 0.94mmol) and Na₂CO₃ (2 M, 0.63 mL). The solution was heated at reflux underargon overnight. The reaction mixture was cooled, diluted with water,extracted with CH₂Cl₂ (3×50 mL). The organic layers were combined,washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thesolution was purified by flash column chromatography on silica gelfollowed by flash column chromatography on reversed phase silica to give50 (0.09 g, 60%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.82 (d,2H), 7.58-7.42 (m, 5H), 7.30-7.19 (m, 2H), 7.01 (s, 1H), 6.11 (s, 1H),4.91 (d, 1H), 4.81 (s, 2H), 4.62-4.58 (m, 1H), 3.92-3.80 (m, 2H),3.66-3.60 (m, 1H), 1.66-1.48 (m, 8H), 1.04-0.99 (t, 3H); CI MS m/z=471[C₂₇H₃₀N₆O₂+H]⁺.

Example 38 Preparation of Compound 52

To compound 4 (0.46 g, 1.20 mmol) was added1-amino-1-cyclopentanemethanol (51, 1.0 g, 8.61 mmol) and EtOH (2 mL)and the mixture was heated in an oil bath at 150° C. for 60 h. The brownsolution was cooled and heated again at 150° C. for 48 h. The reactionmixture was cooled and concentrated in vacuo. The reaction mixture waspurified by flash column chromatography on silica gel to give 52 (0.39g, 71%) as a tan solid: ¹H NMR (300 MHz, CDCl₃) δ 7.48-7.40 (m, 3H),7.29-7.20 (m, 2H), 6.88 (s, 1H), 6.25 (s, 1H), 5.10 (s, 1H), 4.72 (s,2H), 4.63-4.51 (m, 1H), 3.78 (s, 2H), 2.10-1.65 (m, 8H), 1.54 (d, 6H);CI MS m/z=459 [C₂₁H₂₇BrN₆O+H]⁺.

Example 39 Preparation of Compound 53

To a suspension of Pd(PPh₃)₄ (0.07 g, 0.06 mmol) in DME (5 mL) was added52 (0.102 g, 0.22 mmol) and stirred at room temperature for 15 min. Tothis was added phenylboronic acid (0.098 g, 0.80 mmol) and Na₂CO₃ (2 M,0.44 mL). The solution was heated at reflux under argon for 18 h. Thereaction mixture was diluted with water, extracted with CH₂Cl₂ (3×50mL), washed with brine, and dried over Na₂SO₄. The solution was purifiedby flash column chromatography on silica gel followed by flash columnchromatography on reversed phase silica gel to give 53 (0.02 g, 20%): ¹HNMR (300 MHz, CDCl₃) δ 7.59-7.31 (m, 10H), 6.95 (s, 1H), 5.95 (s, 1H),5.10 (s, 1H), 4.79 (s, 2H), 4.61-4.52 (m, 1H), 3.76 (s, 2H), 2.01-1.61(m, 8H), 1.54 (d, 6H); CI MS m/z=457 [C₂₇H₃₂N₆O+H]⁺.

Example 40 Preparation of Compound 54

To compound 3 (0.26 g, 0.67 mmol) was added trans-4-aminocyclohexanolhydrochloride (0.62 g, 4.11 mmol), Et₃N (0.58 mL, 4.16 mmol), andethanol (5 mL). The mixture was heated for 5 h at 135° C. in an oilbath. The temperature increased to 150° C. and heating was continued fora further 48 h. The solution was cooled and evaporated to give a yellowoil: CI MS m/z=459 [C₂₁H₂₇BrN₆O+H]⁺.

Example 41 Preparation of Compound 55

To compound 3 (0.50 g, 1.31 mmol) was added cis-1,2-diaminocyclohexane(1.57 mL, 13.1 mmol) and EtOH (4 mL). The mixture was heated in an oilbath at 150° C. for 6 h. The reaction mixture was concentrated in vacuo.The reaction mixture was purified by column chromatography on silica gelto give 55 (0.49 g, 82%) as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ7.43-7.40 (m, 3H), 7.23 (d, 2H), 6.21 (s, 1H), 5.04 (d, 1H), 4.72 (s,2H), 4.67-4.58 (m, 1H), 4.08-4.05 (m, 1H), 3.17-3.15 (m, 1H), 2.08 (s,2H), 1.65-1.38 (m, 14H); CI MS m/z=458 [C₂₁H₂₈BrN₇+H]⁺.

Example 42 Preparation of Compound 56

To compound 55 (0.10 g, 0.22 mmol) was added 2-(tributylstannyl)pyridine(0.10 g, 0.27 mmol), Pd(PPh₃)₄ (0.05 g, 0.04 mmol), and toluene (5 mL).The solution was degassed with argon for 8 min and heated at 135° C. for3 h. The cooled solution was diluted with water, extracted with CH₂Cl₂(3×50 mL), and the combined organic extracts were washed with brine,dried over Na₂SO₄, filtered, and concentrated. The solution was followedby flash column chromatography (2×) to give the desired product 56 (0.03g, 36%) yellow crystalline solid: ¹H NMR (300 MHz, CDCl₃) δ 8.68 (d,1H), 7.96 (d, 2H), 7.78-7.69 (m, 2H), 7.49 (s, 1H), 7.44 (d, 2H),7.23-7.18 (m, 1H), 6.10 (s, 1H), 5.10-5.00 (m, 1H), 4.83 (s, 2H),4.69-4.60 (m, 1H), 4.20-4.10 (m, 1H), 3.27-3.13 (m, 1H), 2.48 (s, 2H),1.78-1.42 (m, 14H); CI MS m/z=457 [C₂₆H₃₂N₈+H]⁺.

Example 43 Preparation of Compound 57

To compound 1 (0.50 g, 1.31 mmol) was added trans-1,2-diaminocyclohexane(2.52 mL, 21 mmol), and EtOH (6 mL). The reaction mixture was placed inan oil bath and heated to 190° C. for 25 h. The reaction mixture wasremoved from the heat and cooled to room temperature, concentrated forpurification. The reaction mixture was purified by column chromatographyon silica gel to yield 57 (520 mg, 87%) as an off white foam: ¹H NMR(300 MHz, DMSO) δ 7.95 (bs, 1H), 7.85 (s, 1H), 7.50 (d, 2H), 7.34 (d,2H), 6.17 (d, 1H), 4.70-4.40 (m, 1H), 2.00-1.71 (m, 4H), 1.70-1.52 (m,2H), 1.41 (d, 6H), 1.30-0.92 (m, 4H); API MS m/z=460 [C₂₁H₂₈N₇Br+H]⁺.

Example 44 Preparation of Compound 58

Compound 57 (0.15 g, 0.32 mmol) was added to a suspension of Pd(PPh₃)₄(0.11 g, 0.1 mmol) in DME (7 mL) and stirred at room temperature for 15min. Phenylboronic acid (0.14 g, 1.14 mmol) was added followed by theNa₂CO₃ (2M, 0.62 mmol). The reaction mixture was refluxed under argonfor 18 h and allowed to stir at room temperature for 51 h. It was thendiluted with water, extracted with CH₂Cl₂, washed with brine, and thenextracted with CH₂Cl₂. The organic layer was evaporated, dried overanhydrous Na₂SO₄, purified by column chromatography, and placed in vacuofor 18 h to give 58 (0.10 g, 72%) as a white solid: ¹H NMR (300 MHz,CDCl₃) δ 7.62-7.35 (m, 10H), 5.92 (br, 1H), 4.83 (br, 2H), 4.74-4.56 (m,2H), 3.77-3.55 (m, 1H), 2.55-2.43 (m, 1H), 2.16-1.91 (m, 2H), 1.73 (br,2H), 1.52 (d, 6H), 1.37-1.09 (m, 6H); API MS m/z=456 [C₂₇H₃₃N₇+H]⁺.

Example 45 Preparation of Compound 59

To compound 57 (460 mg, 1.0 mmol) in solution with CH₂Cl₂ (2 mL) wasadded acetic anhydride (0.44 mL, 4.6 mmol), catalytic DMAP, and pyridine(0.5 mL). The mixture was stirred at room temperature for 2.5 h. Themixture was diluted with CH₂Cl₂, washed with 2N HCl, and the combinedorganics were then washed with NaHCO₃. The organics were then washedwith brine, dried over Na₂SO₄, filtered, and concentrated to give 59(472 mg, 94%) as an off white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.76(s, 1H), 7.42 (d, 2H), 7.29 (d, 2H), 4.68-4.40 (m, 1H), 4.10 (s, 3H),3.61-3.40 (m, 2H), 2.15-1.80 (m, 2H), 1.74-1.55 (m, 4H), 1.45 (d, 6H),1.35-1.05 (m, 4H); API MS m/z=500 [C₂₃H₃₀BrN₇O+H]⁺.

Example 46 Preparation of Compound 60

To a suspension of Pd(PPh₃)₄ (0.11 g, 0.1 mmol) in DME (7 mL) was addedcompound 59 (0.15 g, 0.3 mmol) and stirred at room temperature for 15min under argon. Phenylboronic acid (0.13 g, 1.06 mmol) was added,followed by Na₂CO₃ (2M, 0.62 mL). The reaction mixture was refluxedunder argon for 18 h. The reaction mixture was then diluted with H₂O,extracted with CH₂Cl₂, washed with brine, and extracted with CH₂Cl₂. Theorganic layer was dried over anhydrous Na₂SO₄, purified by columnchromatography, concentrated in vacuo for 18 h to yield 60 (61 mg, 42%):¹H NMR (300 MHz, DMSO-d₆) δ 7.96 (s, 1H), 7.72 (s, 1H), 7.51 (t, 3H),7.40-7.28 (m, 3H), 7.28-7.13 (m, 2H), 5.84 (br, 1H), 4.46 (br, 3H), 3.47(br, 2H), 1.83 (br, 1H), 1.62 (s, 4H), 1.43 (d, 6H), 0.12 (s, 3H); APIMS m/z=498 [C₂₉H₃₅N₇O+H]⁺.

Example 47 Preparation of Compound 61

To compound 3 (0.58 g, 1.53 mmol) was added trans-1,4-diaminocyclohexane(1.78 g, 15.6 mmol), and EtOH (4 mL). The mixture was heated in an oilbath at 150° C. for ca. 60 h. The reaction mixture was purified bycolumn chromatography on silica gel to yield 61 (0.48 g, 68%) as an offwhite solid: mp 122-125° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.43 (s, 1H),7.40 (d, 2H), 7.20 (d, 2H), 6.27 (s, 1H), 4.75-4.68 (m, 2H), 4.67-4.58(m, 2H), 3.81-3.68 (m, 1H), 3.45 (s, 2H), 2.88-2.75 (m, 1H), 2.18-2.05(m, 2H), 2.05-1.89 (m, 2H), 4.52 (d, 6H), 1.45-1.13 (m, 4H); CI MSm/z=459 [C₂₁H₂₈BrN₇+H]⁺.

Example 48 Preparation of Compound 62

Amine 61 (53 mg, 0.12 mmol) was dissolved in CH₂Cl₂ (2 mL) and pyridine(5 mL). Acetic anhydride (0.05 g, 0.53 mmol) and DMAP (few crystals)were added. The reaction mixture was allowed to stir at room temperaturefor 2.25 h. The reaction mixture was diluted with CH₂Cl₂, washed with 2NHCl, NaHCO₃, dried over MgSO₄, filtered, and evaporated to yield 62(0.05 g, 78%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.50-7.20 (m,5H), 6.02 (br, 1H), 5.29-5.20 (m, 1H), 4.72 (d, 2H), 4.66-4.54 (m, 2H),3.72 (br, 2H), 2.18-2.06 (m, 2H), 2.06-1.91 (m, 2H), 1.97 (s, 3H), 1.54(d, 6H), 1.36-1.15 (m, 4H); API MS m/z=500 [C₂₃H₃₀BrN₇O+H]⁺.

Example 49 Preparation of Compound 64

Compound 61 (0.05 g, 0.11 mmol) was dissolved in CH₂Cl₂ (3 mL) and Et₃N(2 mL) and placed in an ice bath for 10 min. Compound 63 (0.06 g, 0.22mmol) was dissolved in CH₂Cl₂ (2 mL), added dropwise, and rinsed withCH₂Cl₂ (1.5 mL). The ice bath was removed after 20 min and the reactionwas allowed to stir for 7 d. The reaction mixture was diluted withCH₂Cl₂, washed with 2N HCl until the aqueous layer was acidic, washedwith NaHCO₃, dried over MgSO₄, and evaporated. The desired product wasisolated by column chromatography and dried in vacuo to yield 64 (0.04g, 50%) as a green solid: ¹H NMR (300 MHz, CDCl₃) δ 8.53 (d, 1H),8.32-8.20 (m, 2H), 7.59-7.35 (m, 4H), 7.23-7.11 (m, 4H), 6.02 (br, 1H),4.69-4.45 (m, 5H), 3.57 (br, 1H), 3.12 (br, 1H), 2.87 (s, 1H), 1.97 (br,2H), 1.75 (br, 2H), 1.48 (d, 6H), 1.27-0.97 (m, 4H); API MS m/z=693[C₃₃H₃₉BrN₈O₂S+H]⁺.

Example 50 Preparation of Compound 65

Compound 61 (0.05 g, 0.11 mmol) was dissolved in CH₂Cl₂ (3 mL) and Et₃N(2 mL) and placed in an MeOH/ice bath. Methanesulfonyl chloride (0.012mg, 0.11 mmol) in CH₂Cl₂ (2.3 mL) was slowly added. The reaction mixtureand ice bath was allowed to come to room temperature. After 1.5 h, thereaction mixture was diluted with CH₂Cl₂, washed with 2N HCl until theaqueous layer was acidic. The organic layer was washed with NaHCO₃,dried over MgSO₄, filtered, and evaporated. The product was purified bycolumn chromatography, and dried in vacuo for 14 h to yield 65 (13 mg,24%) as an off-white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.50-7.17 (m, 5H),5.90 (br, 1H), 4.75-4.57 (m, 3H), 4.11 (d, 1H), 3.69 (br, 1H), 3.30 (br,1H), 2.99 (s, 3H), 2.18-2.03 (m, 4H), 1.69 (d, 6H), 1.42-1.15 (m, 5H);API MS m/z=538 [C₂₂H₃₀BrN₇O₂S+H]⁺.

Example 51 Preparation of Compound 66

Compound 61 (0.05 g, 0.11 mmol) was dissolved in toluene (4 mL).2-Acetylphenylisocyanate (0.024 g, 0.15 mmol) diluted with toluene (1mL) and added to compound 61. Toluene (6 mL) was added to the reactionmixture. The reaction mixture was placed under reflux for 19 h. Theproduct was purified by column chromatography, concentrated, and driedin vacuo for 23 h to yield 66 (42 mg, 62%) as an off-white solid: ¹H NMR(300 MHz, CDCl₃) δ 7.87-7.20 (m, 9H), 6.41 (s, 1H), 5.86 (br, 1H),4.75-4.54 (m, 4H), 3.69 (br, 1H), 2.60 (s, 3H), 2.12 (br, 4H), 1.51 (d,6H), 1.42-1.15 (m, 5H); API MS m/z=619 [C₃₀H₃₅BrN₈O₂+H]⁺.

Example 52 Preparation of Compound 67

Compound 61 (0.04 g, 0.10 mmol) was dissolved in CH₂Cl₂ (2 mL) andpyridine (0.5 mL). Cyclopropanecarbonyl chloride (0.05 g, 0.44 mmol) wasadded along with DMAP (small amount). The reaction mixture was allowedto stir at room temperature for 2.25 h. The reaction mixture was dilutedwith CH₂Cl₂, washed with 2N HCl, saturated NaHCO₃, dried over MgSO₄,filtered, and evaporated. The product was isolated by columnchromatography to yield 67 (0.03 g, 63%) as a white solid: ¹H NMR (300MHz, CDCl₃) δ 7.50-7.20 (m, 5H), 5.96 (br, 1H), 5.41 (d, 1H), 4.72 (d,2H), 4.66-4.54 (m, 2H), 3.72 (br, 2H), 2.18-1.97 (m, 4H), 1.51 (d, 6H),1.36-1.15 (m, 5H), 1.06-0.88 (m, 2H), 0.79-0.67 (m, 2H); API MS m/z=526[C₂₅H₃₂BrN₇O+H]⁺.

Example 53 Preparation of Compound 69

To a solution of 4-biphenylcarboxaldehyde (1.0 g, 5.49 mmol) in MeOH (20mL) was added NaBH₃CN (0.69 g, 11.0 mmol), and NH₄OH (15 mL) and themixture was stirred at room temperature overnight. To this added HCl andextracted with CHCl₃. The resulting aqueous layer was brought to pH>7with sodium bicarbonate and then extracted with CHCl₃. The solution wasdried with MgSO₄, filtered, and evaporated to give 69 (200 mg) as awhite solid: EI MS m/z=183 [C₁₃H₁₃N]⁺.

Example 54 Preparation of Compound 69

To compound 70 (2.75 g, 13.9 mmol) was added anhydrous THF (60 mL),heated to reflux, and kept under nitrogen. 1M Borane-THF (69.7 mL) wasadded dropwise to 70 through an addition funnel resulting in ahomogeneous solution. The solution was refluxed for 18 h. The reactionmixture was cooled in an ice water bath and quenched with H₂O, 2N HCl(20 mL), followed by 3N NaOH (60 mL). The reaction mixture was extractedwith EtOAc (3×). The organic extracts were washed with brine, and driedover sodium sulfate. The crude product was concentrated, dissolved inMeOH, and HCl gas was bubbled through the solution. The solution wasfiltered in vacuo to give 69 as a white solid: ¹H NMR (300 MHz, CD₃OD) δ7.71 (d, 2H), 7.63 (d, 2H), 7.52 (d, 2H), 7.47-7.30 (m, 3H), 4.13 (s,2H).

Example 55 Preparation of Compound 71

To compound 1 (6.8 g, 36.0 mmol) and 69 (8.0 g, 36.5 mmol) was added H₂O(60 mL) and Hünigs base (9.0 g, 70.0 mmol). The mixture was stirred andheated to reflux for 5 h during which time H₂O (50 mL) was added as thereaction continued to thicken. The crude product was collected byfiltration, washed with H₂O (500 mL) and EtOH (2×30 mL), air dried, anddried in vacuo to give 71 (11.1 g, 92%): mp 267-269° C.

Example 56 Preparation of Compound 72

Compound 71 (4.7 g, 14.0 mmol), K₂CO₃ (15.0 g, 109 mmol), DMSO (80 mL),and 2-iodopropane (9.4 g, 55.0 mmol) were combined and stirredovernight. H₂O and EtOAc were added. The EtOAc layer was separated andwashed with brine (3×). The EtOAc solution was dried with MgSO₄,concentrated, and crystallized from EtOAc to give 72 (3.5 g, 66%): mp139-140° C.

Example 57 Preparation of Compound 73

Compound 72 (2.00 g, 5.30 mmol) and (R)-(−)-2-amino-1-butanol (10.8 g,121 mmol) were combined in a sealed tube, and heated in an oil bath at190° C. for 2 h. The solution was cooled to 60° C., diluted in EtOAc,washed with brine (4×), dried with Na₂SO₄, and concentrated.Purification by column chromatography on SiO₂ gave the desired product73 (1.72 g, 75%) as a foam: ¹H NMR (300 MHz, CDCl₃) δ 7.65-7.10 (m, 9H),6.40-6.10 (bs, 1H), 5.05-4.85 (m, 1H), 4.85-4.67 (m, 1H), 4.60(heptuplet, 1H), 4.00-3.70 (dd, 2H), 3.76-3.50 (m, 1H), 1.95 (bs, 1H),1.80-1.55 (m, 2H), 1.51 (d, 6H), 1.03 (t, 3H); IR (CH₂Cl₂) 3301, 2969,1601, 1488, 1389, 1255, 762, 698 cm⁻¹; API MS m/z=431 [C₂₅H₃₀N₆O+H]⁺.

Example 58 Preparation of Compound 74

Compound 72 (0.23 g, 0.60 mmol), cis-1,2-diaminocyclohexane (0.72 mL,6.0 mmol), and ethanol (2 mL) were combined in a sealed tube and heatedin an oil bath at 155° C. for 5 d. The ethanol was removed in vacuo andthe crude reaction mixture was filtered through a silica plug. Thereaction mixture was chromatographed on silica gel, the resulting orangesolid was dissolved in CH₂Cl₂ and a portion of activated charcoal wasadded. The solution was filtered through a pad of celite andconcentrated to give 74 as a yellow solid (0.04 g, 27%): ¹H NMR (300MHz, CDCl₃) 7.59-7.31 (m, 10H), 6.00 (s, 1H), 5.09 (d, 1H), 4.83 (s,2H), 4.68-4.62 (m, 1H), 4.11 (s, 1H), 3.70-3.65 (m, 2H), 3.18-3.16 (m,1H), 2.02 (s, 2H), 1.67-1.42 (m, 12H); CI MS m/z=456 [C₂₇H₃₃N₇+H]⁺.

Example 59 Preparation of Compound 75

Compound 72 (0.17 g, 0.45 mmol), trans-1,4-diaminocyclohexane (0.53 g,4.69 mmol), and EtOH (5 mL) were combined in a sealed tube and heated at155° C. for 5 d. The EtOH was removed in vacuo and the crude mixture wassubjected to flash chromatography on silica gel. Recrystallization fromCHCl₃/MeOH gave 75 (5.8 mg) as an off-white crystalline solid: mp110-112° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.58-7.31 (m, 10H), 5.95 (s, 1H),4.88-4.78 (m, 2H), 4.69-4.60 (m, 2H), 3.88-3.78 (m, 1H), 3.07-2.98 (m,1H), 2.26-2.10 (m, 4H), 1.62-1.52 (m, 8H), 1.29-1.15 (m, 4H); CI MSm/z=456 [C₂₇H₃₃N₇+H]⁺.

Example 60 Preparation of Compound 76

Compound 75 (0.05 g, 0.11 mmol) was dissolved in CH₂Cl₂ and the solutioncooled to 0° C. under an argon atmosphere. A catalytic amount of DMAP,triethylamine (50 L, 0.36 mmol), followed by the acetyl chloride (25 L,0.36 mmol) were added to the reaction mixture. The solution was warmedto room temperature and washed with NaHCO₃ (5%), water, and brine. Thesolution was dried over Na₂SO₄ and concentrated. Purification by flashchromatography on silica gel gave 76 (0.028 g, 53%) as a pale yellowsolid: mp 224-225° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.59-7.31 (m, 10H),5.93 (s, 1H), 5.26 (d, 1H), 4.81 (s, 2H), 4.65-4.58 (m, 1H), 3.78-3.75(m, 2H), 2.18-1.99 (m, 4H), 1.95 (s, 3H), 1.77 (s, 1H), 1.53 (d, 6H),1.32-1.22 (m, 4H); CI MS m/z=498 [C₂₉H₃₅N₇O+H]⁺.

Example 61 Preparation of Compound 77

Compound 72 (0.15 g, 0.40 mmol), trans-4-aminocyclohexanol hydrochloride(0.31 g, 1.99 mmol), Et₃N (0.11 mL, 0.8 mmol), and EtOH (5 mL) werecombined and heated in a sealed tube at 155° C. for 4 d. Additionaltrans-4-aminocyclohexanol hydrochloride (0.34 g, 2.2 mmol) andtriethylamine (0.60 mL, 4.3 mmol) were added and the heat was resumed at155° C. overnight. The crude product was purified by flash columnchromatography to give 77 (0.036 g, 20%) as an off-white solid: mp196-200° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.58-7.30 (m, 10H), 5.97 (s, 1H),4.83-4.81 (m, 2H), 4.66-4.60 (m, 2H), 3.82-3.77 (m, 1H), 3.69-3.62 (m,1H), 2.17-2.13 (m, 2H), 2.01-1.97 (m, 2H), 1.68 (s, 1H), 1.53 (d, 6H),1.49-1.20 (m, 4H); CI MS m/z=457 [C₂₇H₃₃N₆O+H]⁺.

Example 62 Preparation of Compound 78

To compound 61 (0.12 g, 0.26 mmol), was added compound 16 (0.12 g, 0.33mmol), and Pd(PPh₃)₄ (0.06 g, 0.056 mmol) and toluene (5 mL). Theresulting mixture was degassed for 10 min with argon. The mixture washeated at 140° C. for 3 h. The cooled solution was diluted withsaturated NaHCO₃ and extracted with CH₂Cl₂ (3×50 mL). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, filtered,and concentrated to give a pale yellow oil which crystallized uponstanding at room temperature. The crude product was purified by columnchromatography and concentrated to give a white solid. The solid wasprecipitated with acetonitrile, filtered, washed with ether and hexaneto give 78 (0.02 g, 18%): ¹H NMR (300 MHz, DMSO-d₆) δ 8.63 (d, 1H), 8.01(d, 1H), 7.93-7.83 (m, 2H), 7.59-7.44 (m, 4H), 7.34-7.29 (m, 1H), 6.25(s, 1H), 4.70-4.60 (m, 2H), 4.57-4.49 (m, 2H), 3.65-3.52 (m, 1H),2.98-2.88 (m, 1H), 1.98-1.90 (m, 4H), 1.48 (d, 6H), 1.42-1.18 (m, 6H);CI MS m/z=457 [C₂₆H₃₂N₈+H]⁺.

Example 63 Preparation of Compound 78

To compound 24 (200 mg, 0.53 mmol) was addedtrans-1,4-diaminocyclohexane (2.00 g, 17 mmol) and EtOH (4 mL). Thereagents were heated in a sealed tube in an oil bath at 170° C. for 18h. The mixture was cooled to 60° C. and partitioned between EtOAc andbrine. The EtOAc layer was separated, washed with brine (3×), dried withNa₂SO₄, and concentrated to give 78 (0.12 g, 50%): mp 135-138° C.; ¹HNMR (300 MHz, CDCl₃) δ 8.03-7.82 (m, 2H), 7.80-7.58 (m, 3H), 7.57-7.30(m, 3H), 7.30-7.05 (m, 1H), 6.20 (bs, 1H), 5.95-4.73 (m, 2H), 4.73-4.45(m, 2H), 3.90-3.60 (m, 1H), 2.80-2.52 (m, 1H), 2.25-1.80 (m, 4H),1.80-1.60 (bs, 3H), 1.52 (d, 6H), 1.38-1.05 (m, 4H); IR (KBr) 3422,2927, 1599, 1489, 1253, 779 cm⁻¹; API MS m/z=457 [C₂₆H₃₂N₈+H]⁺.

Example 64 Preparation of Compound 79

Compound 78 (50 mg, 0.11 mmol) was dissolved in CH₂Cl₂ (2 mL) andstirred at room temperature. Pyridine (0.5 mL), Ac₂O (0.5 mL, 4.9 mmol),and DMAP (few crystals) were added to the reaction mixture and stirredfor 2 h. The solution was diluted in CH₂Cl₂ and washed in 2N HCl. TheHCl layer was concentrated, CH₂Cl₂ was added and the aqueous phaseneutralized with saturated NaHCO₃. The CH₂Cl₂ layer was separated, dried(MgSO₄), and concentrated to give 79 (0.03 g, 55%) as a white solid: ¹HNMR (300 MHz, CDCl₃) δ 8.00-7.80 (m, 2H), 7.81-7.57 (m, 2H), 7.56-7.33(m, 3H), 7.30-7.05 (m, 2H), 6.15-5.90 (bs, 1H), 5.47-5.28 (m, 1H),4.96-4.72 (m, 2H), 4.73-4.45 (m, 2H), 2.25-1.82 (m, 4H), 2.00 (s, 3H),1.54 (d, 6H), 1.40-1.00 (m, 4H); API MS m/z=499 [C₂₈H₃₄N₈O+H]⁺.

Example 65 Preparation of Compound 80

Compound 74 (0.02 g, 0.05 mmol) was dissolved in dry benzene (5 mL) andstirred under a blanket of argon. The solution was cooled in an ice bathand phenylisocyanate (25 L, 0.23 mmol) was added dropwise. The ice bathwas removed and the mixture stirred at room temperature for 0.5 h. Thesolvent was evaporated in vacuo to give a yellow oil. The crude productwas purified by flash column chromatography on silica gel to give 80(0.008 g): ¹H NMR (300 MHz, CDCl₃) δ 7.53-7.30 (m, 10H), 7.13-7.06 (m,4H), 6.98-6.88 (m, 1H), 6.62 (s, 1H), 6.02 (s, 1H), 5.65 (s, 1H), 5.02(d, 1H), 4.85-4.70 (m, 2H), 4.60-4.52 (m, 1H), 4.45-4.40 (m, 1H),4.36-4.22 (m, 2H), 4.00 (s, 1H), 1.91-1.60 (m, 6H), 1.48-1.43 (m, 6H).

Example 66 Preparation of Compound 82

A mixture of 6-chloronicotinamide (2.96 g, 18.9 mmol), phenylboronicacid (2.54 g, 20.8 mmol), and Pd(PPh₃)₄ (643 mg, 0.565 mmol) in toluene(47 mL), ethanol (7 mL) and 2M aqueous sodium carbonate solution (21 mL,43 mmol) was stirred and heated at 90-100° C. under nitrogen for 16 h.The mixture was cooled to room temperature and filtered. The resultingsolid was washed with water (2×20 mL) and dried in vacuo. To the driedsolid was added methanol (50 mL). The mixture was stirred at reflux,cooled to room temperature, and filtered to give the product (90%) as apowder: mp 218-220° C.; ¹H NMR (500 Hz, DMSO-d₆) δ 9.23 (d, J=2.5 Hz,1H), 8.41 (dd, J₁=2.2 Hz, J₂=8.3 Hz, 1H), 8.32 (s, 1H), 8.27 (d, J=7.1Hz, 2H), 8.20 (d, J=8.5 Hz, 1H), 7.74 (s, 1H), 7.66-7.60 (m, 3H).

Example 67 Preparation of Compound 83

To NaBH₄ (0.19 g, 5 mmol) in 1,4-dioxane (4 mL) was added HOAc (0.3 g, 5mmol) in 1,4-dioxane (2 mL) slowly while the flask was cooled with ice.Compound 82 (0.2 g, 1 mmol) was then added. The mixture was stirred atreflux at 100-110° C. for 4 h and the solvent was evaporated. To thismixture was added water (2 mL) slowly. The mixture was extracted withCH₂Cl₂ (4×10 mL), washed with water (3×5 mL), dried with anhydroussodium sulfate, concentrated, and purified by flash chromatography onsilica gel to provide the product as a yellow liquid. This wastriturated with ethanol (1 mL) to provide a white solid which wascollected (60%) and dried: mp 97-99° C.; ¹H NMR (500 Hz, CDCl₃) δ 8.60(d, J=2 Hz, 1H), 7.97-7.95 (m, 2H), 7.72-7.67 (m, 2H), 7.47-7.37 (m,3H), 3.90 (s, 2H), 1.77 (bs, 2H).

Example 68 Preparation of Compound 84

A mixture of 2,6-dichloropurine (1, 0.19 g, 1 mmol), amine 83 (0.39 g,2.15 mmol) in ethanol (13 mL), and water (3 mL) was heated at 100-110°C. under nitrogen for 24 h and then cooled to room temperature. Themixture was concentrated and water (5 mL) was added. A solid wasfiltered and washed with water (2×5 mL) and dried under vacuum to givethe product (80%) as a yellow solid: mp 260° C. (dec); ¹H NMR (500 Hz,DMSO-d₆) δ 13.26 (s, 1H), 8.79 (s, 1H), 8.27 (s, 1H), 8.16 (d, J=7.1 Hz,2H), 8.34 (d, J=7.3 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.63-7.52 (m, 3H),4.81 (s, 2H).

Example 69 Preparation of Compound 85

To a solution of compound 84 (0.34 g, 1 mmol) in DMSO (5 mL), was addedpotassium carbonate (0.7 g, 5 mmol) and 2-iodopropane (0.5 g, 3 mmol).The mixture was stirred at ambient temperature under nitrogen for 24 hand poured into ice water (30 mL). After filtration, the solid waswashed with water (4×5 mL), dried under vacuum to give the crude productas a yellow solid. Flash column chromatography of the crude product onsilica gel and recrystallization provided the pure product (63%) asivory colored crystals: mp 138-139° C.; ¹H NMR (500 Hz, CDCl₃) δ 8.70(d, J=1.5 Hz, 1H), 7.97 (m, 2H), 7.79 (dd, J₁=1.7 Hz, J₂=8.1 Hz, 1H),7.71 (s, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.48-7.39 (m, 3H), 4.87 (s, 2H),4.80 (m, 1H), 1.55 (d, J=6.8 Hz, 6H); CI MS m/z=379 [C₂₀H₁₉ClN₆+H]⁺.Anal. Calcd. for C₂₀H₁₉ClN₆: C, 63.41; H, 5.05; N, 22.18. Found: C,63.75; H, 5.09; N, 21.87.

Example 70 Preparation of Compound 86

To compound 85 (0.1 g, 0.26 mmol) was added trans-1,4-diaminocyclohexane(1 g, 8.8 mmol) and EtOH (2 mL). The reaction mixture was heated in asealed tube in an oil bath at 120° C. The crude product was purified bycolumn chromatography to give 86 (0.08 g, 67%): ¹H NMR (300 MHz, CDCl₃)δ 8.68 (d, 1H), 7.83-7.97 (m, 2H), 7.70-7.83 (m, 1H), 7.55-7.73 (m, 1H),7.30-7.55 (m, 4H), 6.35 (bs, 1H), 4.72-4.95 (m, 2H), 4.50-4.72 (m, 2H),3.63-3.85 (m, 1H), 2.65-2.90 (m, 1H), 2.37-2.63 (bs, 2H), 1.80-2.20 (dd,4H), 1.53 (d, 6H), 0.72-1.42 (m, 4H); API MS m/z=457 [C₂₆H₂₂N₈+H]⁺.

Example 71 Preparation of Compound 87

Compound 86 (0.08 g, 0.18 mmol) was stirred at room temperature inCH₂Cl₂ (3 mL). Pyridine (100 mg, 0.82 mmol) was added followed by Ac₂O(100 mg, 0.98 mmol) and DMAP (few crystals). After 2 h, more CH₂Cl₂ (3mL) was added and the mixture was washed carefully with 2N HCl (10drops), and saturated NaHCO₃. After separation of the CH₂Cl₂ layer, theorganic phase was then dried with Na₂SO₄ and concentrated to give 87 (80mg, 92%): ¹H NMR (300 MHz, CDCl₃) δ 8.72 (s, 1H), 8.30-7.03 (m, 9H),5.75-5.38 (m, 1H), 5.02 (bs, 1H), 4.83 (bs, 2H), 4.72-4.40 (m, 1H), 3.73(bs, 2H), 2.52-1.83 (m, 4H), 1.98 (s, 3H), 1.52 (d, 6H), 1.50-1.00 (m,4H); API MS m/z=499 [C₂₈H₃₄N₈O+H]⁺.

Example 72 Preparation of Compound 88

Compound 85 (0.05 g, 0.13 mmol) and (R)-(−)-2-amino-1-butanol (0.50 g,5.6 mmol) were combined in a sealed tube and heated in an oil bath at190° C. for 2 h then cooled to room temperature. The mixture waspartitioned between EtOAc and brine, washed with brine (3×), dried withNa₂SO₄, and concentrated. The mixture was allowed to stand over theweekend and then purified by column chromatography on SiO₂ to give 88(0.01 g, 17%) as a foam: ¹H NMR (300 MHz, CDCl₃) δ 8.70 (s, 1H),8.05-7.82 (m, 2H), 7.82-7.55 (m, 2H), 7.57-7.30 (m, 4H), 6.55 (bs, 1H),5.00-4.88 (s, 1H), 4.78 (s, 2H), 4.60 (heptuplet, 1H), 3.98-3.83 (m,1H), 3.84-3.70 (m, 1H), 3.70-3.50 (m, 1H), 2.90 (bs, 1H), 1.75-1.55 (m,2H), 1.53 (d, 6H), 1.00 (t, 3H); API MS m/z=432 [C₂₄H₂₉N₇O+H]⁺.

Example 73 Preparation of Compound 89

A mixture of 6-chloronicotinamide (2.5 g, 16 mmol), crude2-trimethylstannylpyridine (5.8 g, 24 mmol), and PdCl₂(PPh₃)₂ (560 mg,0.8 mmol) in DMF (35 mL) was heated at 150-160° C. in a pressure tubefor 17 h. The DMF was distilled off under reduced pressure and theresidue was extracted with ethyl acetate (6×30 mL) and concentrated. Theresidue was treated with methanol (15 mL) and a solid separated whichwas filtered and dried to give the product (40%) as a powder: mp237-240° C.; ¹H NMR (500 Hz, DMSO-d₆) 9.22 (d, J=2.2 Hz, 1H), 8.83 (m,1H) 8.57-8.53 (m, 2H), 8.48-8.46 (m, 1H), 8.38 (s, 1H), 8.11-8.07 (m,1H), 7.78 (s, 1H), 7.63-7.60 (m, 1H).

Example 74 Preparation of Compound 90

To NaBH₄ (0.2 g, 5 mmol) in 1,4-dioxane (4 mL) was added HOAc (0.29 g, 5mmol) in 1,4-dioxane (2 mL) slowly while the flask was cooled with ice.Compound 89 (0.199 g, 1 mmol) was then added. The mixture was stirred atreflux at 100-110° C. for 4 h and the solvent was evaporated. To thismixture was added water (2 mL) slowly. The mixture was extracted withCH₂Cl₂ (4×10 mL), washed with water (3×5 mL), dried with anhydroussodium sulfate, filtered, concentrated, and purified by flashchromatography on silica gel to provide the product as a yellow liquid.This was triturated with ethanol (1 mL) and a white solid (32%) wascollected and dried: mp 109-112° C.; ¹H NMR (500 Hz, CDCl₃) δ 8.63 (m,1H), 8.58 (s, 1H), 8.32 (m, 2H), 7.77 (m, 2H), 7.25 (m, 1H), 3.91 (s,2H), 1.94 (s, 2H).

Example 75 Preparation of Compound 91

A mixture of 2,6-dichloropurine (1, 0.2 g, 1 mmol), compound 90 (0.4 g,2.2 mmol) in ethanol (13 mL), and water (3 mL) was heated at 100-110° C.under nitrogen for 24 h and then cooled to room temperature. The mixturewas concentrated and water (5 mL) was added. A solid was filtered andwashed with water (2×5 mL) and dried under vacuum to give the product(83%) as a yellow solid: mp 248° C. (dec); ¹H NMR (500 Hz, DMSO-d₆) δ13.27 (s, 1H), 8.81 (s, 1H), 8.78 (d, J=4.1 Hz, 1H), 8.47 (m, 2H), 8.28(s, 1H), 8.06-8.01 (m, 2H), 7.50 (m, 1H), 4.84 (s, 2H).

Example 76 Preparation of Compound 92

To the solution of compound 91 (0.35 g, 1 mmol) in DMSO (5 mL), addedpotassium carbonate (0.68 g, 5 mmol) and 2-iodopropane (0.49 g, 3 mmol).The mixture was stirred at ambient temperature under nitrogen for 24 hand poured into ice water (30 mL). After filtration, the solid waswashed with water (4×5 mL), dried under vacuum to give the crude productas a yellow solid. Flash column chromatography of the crude product onsilica gel and recrystallization provided the pure product (64%) aswhite crystals: mp 150-151° C.; ¹H NMR (500 Hz, CDCl₃) δ 8.71 (d, J=1.9Hz, 1H), 8.67 (m, 1H), 8.38-8.36 (m, 2H), 7.86-7.79 (m, 2H), 7.75 (s,1H), 7.30 (m, 1H), 4.91 (s, 2H), 4.82 (m, 1H), 1.57 (d, J=6.8 Hz, 6H);CI MS m/z=380 [C₁₉H₁₈ClN₇+H]⁺. Anal. Calcd. for C₁₉H₁₈ClN₇: C, 60.08; H,4.78; N, 25.81. Found: C, 59.76; H, 4.72; N, 25.57.

Example 77 Preparation of Compound 93

Compound 92 (150 mg, 0.39 mmol), trans-1,4-diaminocyclohexane (1.50 g,13.1 mmol), and EtOH (30 mL) were heated to 120° C. for 26 h in a sealedtube. The mixture was cooled, additional EtOAc was added, washed withbrine, dried over Na₂SO₄, and concentrated to give 93 (170 mg, 94%) as awaxy solid: ¹H NMR (300 MHz, CDCl₃) δ 8.77-8.60 (m, 1H), 8.44-8.27 (m,2H), 7.90-7.75 (m, 2H), 7.50 (s, 1H), 7.36-7.22 (m, 2H), 6.27 (bs, 1H),4.96-4.73 (m, 2H), 4.73-4.52 (m, 2H), 3.84-3.60 (m, 1H), 2.80-2.57 (m,1H), 2.22-2.00 (m, 2H), 2.00-1.67 (m, 5H), 1.54 (d, 6H), 1.38-1.05 (m,4H); API MS m/z=458 [C₂₅H₃₁N₉+H]⁺.

Example 78 Preparation of Compound 94

Compound 93 (0.15 g, 0.33 mmol) was dissolved in CH₂Cl₂ (6 mL) and thenpyridine (0.200 g, 1.64 mmol) followed by Ac₂O (0.200 g, 1.96 mmol) andDMAP (few crystals) were added. The reaction mixture was stirred for 2h, washed with 2N HCl and NaHCO₃, extracted with CH₂Cl₂, dried withNa₂SO₄, and concentrated to give 94 (0.17 g, 69%) as a solid: mp141-145° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.80-8.63 (m, 1H), 8.45-8.25 (t,2H), 7.95-7.73 (m, 1H), 7.52 (s, 1H), 7.35-7.20 (m, 2H), 6.20 (bs, 1H),5.50-5.30 (m, 1H), 4.98-4.75 (m, 2H), 4.75-4.50 (m, 2H), 3.84-3.60 (m,2H), 2.27-1.87 (m, 4H), 2.00 (s, 3H), 1.52 (d, 6H), 1.40-1.10 (m, 4H);API MS m/z=499 [C₂₇H₃₃N₉O+H]⁺.

Example 79 Preparation of Compound 95

DME (3 mL), tris(dibenzylideneacetone)dipalladium (0.01 g, 0.01 mmol),and PPh₃ (0.04 g, 0.15 mmol) were added to a round bottomed flaskequipped with a condensor and maintained under an argon atmosphere. Tothe solution was added compound 11 (0.13 g, 0.25 mmol). 3-Fluorobenzeneboronic acid (0.123 g, 0.9 mmol) was dissolved in a solution of 2MNa₂CO₃ (0.6 mL) and DME (1 mL), and added to the reaction mixture. Themixture was stirred under argon and refluxed for 19 h then stirred atroom temperature for 22 h. The reaction mixture was diluted with H₂O,extracted with CH₂Cl₂, washed with brine. The organic layer was driedover Na₂SO₄ and evaporated. The reaction mixture was purified twice bycolumn chromatography and dried under high vacuum to give a white solid(17 mg, 14%): ¹H NMR (300 MHz, CDCl₃) δ 7.56-7.32 (m, 8H), 7.08-6.99 (m,1H), 5.86 (br, 1H), 4.83 (d, 2H), 4.71-4.56 (m, 1H), 3.77 (br, 2H), 2.70(br, 1H), 2.12 (d, 1H), 1.88 (d, 1H), 1.51 (d, 6H), 1.22 (d, 5H),0.94-0.70 (m, 3H); API MS m/z=474 [C₂₇H₃₂FN₇+H]⁺.

Example 80 Preparation of Compound 96

A stock solution of acetic anhydride was made by mixing CH₂Cl₂ (16 mL),pyridine (4 mL), and Ac₂O (0.16 mL). To this stock solution (1.5 mL) wasadded compound 95 (0.01 g, 0.02 mmol) followed by DMAP (few crystals).The reaction mixture was allowed to stir at room temperature for 26 h.The reaction mixture was then diluted with CH₂Cl₂, washed with 2N HCluntil the aqueous layer was acidic, washed with NaHCO₃, dried overMgSO₄, evaporated, and dried in vacuo for 15 h to give a white solid (11mg, 92%): ¹H NMR (300 MHz, CDCl₃) δ 8.65 (br, 1H), 7.77-7.17 (m, 8H),7.11-6.99 (m, 1H), 5.14 (br, 2H), 4.90 (br, 1H), 4.69 (br, 1H), 3.78(br, 2H), 2.09 (br, 3H), 1.94 (s, 2H), 1.57 (d, 6H), 1.42 (br, 4H), 1.24(s, 2H), 0.94-0.76 (m, 1H); CI MS m/z=516 [C₂₉H₃₄FN₇O+H]⁺.

Example 81 Preparation of Compound 97

A stock solution of acetic anhydride was made by mixing CH₂Cl₂ (16 mL),pyridine (4 mL), and Ac₂O (0.16 mL). To this stock solution (1.5 mL) wasadded compound 13 (0.01 g, 0.02 mmol) followed by DMAP (few crystals).The reaction mixture was allowed to stir at room temperature for 2 h.The reaction mixture was then diluted with CH₂Cl₂, washed with 2N HCluntil it was acidic, washed with NaHCO₃, dried over MgSO₄, andevaporated to give a white solid (8 mg, 89%): ¹H NMR (300 MHz, CDCl₃) δ8.78 (d, 1H), 8.44 (t, 1H), 7.95 (t, 2H), 7.69-7.45 (m, 5H), 5.30 (br,2H), 4.84 (br, 1H), 4.68 (br, 1H), 3.78 (br, 2H), 2.39 (s, 3H), 2.10(br, 4H), 1.96 (s, 2H), 1.57 (br, 10H), 1.25 (s, 2H), 0.88 (br, 1H); APIMS m/z=512 [C₃₀H₃₇N₇O+H]⁺.

Example 82 Preparation of Compound 98

DME (3 mL), tris(dibenzylideneacetone)dipalladium (0.01 g, 0.01 mmol),and PPh₃ (0.04 g, 0.15 mmol) were added to a round bottom flask equippedwith condensor and maintained under an argon atmosphere. Iodide 11 (0.13g, 0.26 mmol), and 3-chlorobenzene boronic acid (0.15 g, 0.93 mmol) wasdissolved in 2M Na₂CO₃ (0.6 mL) and DME (1 mL). This was then added tothe reaction mixture and refluxed for 19.5 h then stirred at roomtemperature for 30 h. The reaction mixture was then diluted with H₂O,extracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄, filtered,and evaporated. The reaction mixture was purified by columnchromatography (3×) and evaporated. The product was triturated inhexanes, filtered, and dried in vacuo for 1 h to give a white solid (16mg): ¹H NMR (300 MHz, CDCl₃) δ 7.56-7.38 (m, 9H), 6.01 (br, 1H), 4.80(d, 2H), 4.71-4.62 (m, 1H), 3.77 (br, 2H), 2.73 (br, 1H), 2.19-2.04 (m,1H), 1.94-1.85 (m, 1H), 1.51 (d, 6H), 1.24 (d, 5H), 0.91-1.76 (m, 3H);API MS m/z=490 [C₂₇H₃₂ClN₇+H]⁺.

Example 83 Preparation of Compound 99

A stock solution of acetic anhydride was made by mixing CH₂Cl₂ (16 mL),pyridine (4 mL), and Ac₂O (0.16 mL). To this solution (1.5 mL) was addedcompound 98 (0.01 g, 0.02 mmol), followed by DMAP (few crystals). Thereaction mixture was allowed to stir at room temperature for 2 h. Thereaction mixture was diluted with CH₂Cl₂, washed with 2N HCl until theaqueous layer was acidic, washed with NaHCO₃, dried over MgSO₄,filtered, and evaporated to give a white solid (0.01 g, 83%): ¹H NMR(300 MHz, CDCl₃) δ 7.65-7.35 (m, 8H), 7.26-7.14 (m, 1H), 5.23 (br, 1H),4.66 (br, 1H), 3.78 (br, 2H), 2.18-2.00 (m, 4H), 1.94 (s, 3H), 1.54 (d,6H), 1.24 (s, 5H), 0.94-0.69 (m, 3H); API MS m/z=532 [C₂₉H₃₄ClN₇O+H]⁺.

Example 84 Preparation of Compound 100

A stock solution of acetic anhydride was made by mixing CH₂Cl₂ (16 mL),pyridine (4 mL), and Ac₂O (0.16 mL). To compound 14 (0.02 g, 0.03 mmol)was added this solution (2 mL), followed by DMAP (few crystals). Thereaction mixture was allowed to stir at room temperature for 3 h. Thereaction mixture was diluted with CH₂Cl₂, washed with 2N HCl until theaqueous layer was acidic, washed with NaHCO₃, filtered, and evaporatedto give a white solid (8 mg, 44%): ¹H NMR (300 MHz, CDCl₃) δ 7.41-7.32(m, 7H), 7.26-7.14 (m, 1H), 5.96 (br, 1H), 5.23 (d, 1H), 4.84 (br, 2H),4.69-4.54 (m, 1H), 3.75 (br, 1H), 2.21-2.12 (m, 1H), 2.09-1.96 (m, 1H),1.97 (s, 3H), 1.54 (d, 6H), 1.36-1.15 (m, 5H), 0.85 (br, 3H); API MSm/z=550 [C₂₉H₃₃ClFN₇O+H]⁺.

Example 85 Preparation of Compound 101

DME (3 mL), tris(dibenzylideneacetone)dipalladium (0.01 g, 0.01 mmol),and PPh₃ (0.04 g, 0.15 mmol) were added to a round bottomed flaskequipped with a condensor and maintained under an argon atmosphere.Compound 10 (0.13 g, 0.26 mmol) and 4-fluorobenzene boronic acid (0.13g, 0.95 mmol) was dissolved in 2M Na₂CO₃ (0.6 mL) and DME (1 mL). Thiswas then added to the reaction mixture and refluxed for 19 h thenstirred at room temperature for 72 h. The reaction mixture was thendiluted with H₂O, extracted with CH₂Cl₂, washed with brine, dried overNa₂SO₄, filtered, and evaporated. The reaction mixture was purified bycolumn chromatography on silica gel to give a white solid (17 mg, 14%):¹H NMR (300 MHz, CDCl₃) δ 7.56-7.38 (m, 8H), 7.11 (t, 1H), 5.81 (br,1H), 4.81 (d, 2H), 4.69-4.57 (m, 1H), 3.78 (br, 2H), 2.69 (br, 1H), 2.12(br, 1H), 1.88 (br, 1H), 1.54 (d, 6H), 1.33-1.12 (m, 5H), 0.85 (br, 3H);API MS m/z=474 [C₂₇H₃₂FN₇+H]⁺.

Example 86 Preparation of Compound 102

A stock solution of acetic anhydride was made by mixing CH₂Cl₂ (16 mL),pyridine (4 mL), and Ac₂O (0.16 mL). To the solution (1.4 mL) was addedcompound 101 (0.01 g, 0.02 mmol), followed by DMAP (few crystals). Thereaction mixture was allowed to stir at room temperature for 2.5 h. Thereaction mixture was diluted with CH₂Cl₂, washed with 2N HCl until theaqueous layer was acidic, and washed with saturated NaHCO₃. The organiclayer was dried over MgSO₄ and evaporated to give a product (3 mg). TheNaHCO₃ layer was further extracted with EtOAc (2×), the organic layerswere combined, dried over MgSO₄, evaporated to give product 102 (2 mg).The products were combined using EtOAc, evaporated, and dried in vacuofor 15 h to give product 102 (5 mg, 50%): ¹H NMR (300 MHz, CDCl₃) δ7.71-7.08 (m, 9H), 5.29 (br, 2H), 4.84 (br, 1H), 4.66 (br, 1H), 3.78(br, 2H), 2.09 (br, 4H), 1.97 (s, 1H), 1.57 (br, 3H), 1.24 (d, 6H), 0.87(br, 5H); API MS m/z=516 [C₂₉H₃₄FN₇O+H]⁺.

Example 87 Preparation of Compound 103

Compound 30 (0.10 g, 0.27 mmol) and trans-1,4-diaminocyclohexane (0.48g, 4.2 mmol) were combined with EtOH (2 mL) in a sealed tube and heatedat 190° C. for 24 h, and then stirred at room temperature for 46 h. Thereaction mixture was purified by column chromatography and dried invacuo to give 103 as a white solid (0.10 g, 81%): ¹H NMR (300 MHz,CDCl₃) δ 8.83 (d, 1H), 8.58 (t, 1H), 7.87-7.83 (m, 1H), 7.55-7.47 (m,5H), 7.38-7.33 (m, 1H), 5.96 (br, 1H), 4.82 (d, 2H), 4.68-4.59 (m, 1H),3.75 (br, 2H), 2.69 (br, 1H), 2.14 (d, 2H), 1.86 (d, 2H), 1.54 (d, 6H),1.31-1.18 (m, 5H); API MS m/z=457 [C₂₆H₃₂N₈+H]⁺.

Example 88 Preparation of Compound 104

A stock solution of acetic anhydride was made by mixing CH₂Cl₂ (16 mL),pyridine (4 mL), and Ac₂O (0.16 mL). To the solution (3.1 mL) was addedcompound 103 (0.02 g, 0.04 mmol), followed by DMAP (few crystals). Thereaction mixture was allowed to stir at room temperature for 2.5 h. Thereaction mixture was evaporated, dried in vacuo for 19 h, and purifiedby column chromatography to give a white solid (0.02 g): ¹H NMR (300MHz, CDCl₃) δ 8.83 (d, 1H), 8.59 (t, 1H), 7.85 (d, 1H), 7.55-7.47 (m,5H), 7.38-7.34 (m, 1H), 5.89 (br, 1H), 5.25 (d, 2H), 4.85 (br, 1H),4.66-4.61 (m, 1H), 3.77 (br, 2H), 2.15 (br, 2H), 2.05 (br, 2H), 1.97 (s,2H), 1.54 (d, 6H), 1.33-1.25 (m, 5H), 0.88 (br, 1H); API MS m/z=499[C₂₈H₃₄N₈O+H]⁺.

Example 89 Preparation of Compound 106

Compound 72 (0.30 g, 0.80 mmol) and compound 105 (1.15 g, 6.50 mmol)(Gardiner, J. M., et al. Tetrahedron, 42(11):515 (1995), which is herebyincorporated by reference, were combined with EtOH (7 mL) and allowed toreflux for 23 h. Triethylamine (1 mL) was added and the reaction wasrefluxed further for another 21 h. The reaction mixture was thentransferred to a sealed tube and EtOH (3 mL) was added. The reactionmixture was heated further at 100° C. for 3 h. The mixture was purifiedby column chromatography to give 105 (0.13 g): ¹H NMR (300 MHz, CDCl₃) δ7.57-7.26 (m, 10H) 5.58 (br, 1H), 5.10 (br, 1H), 4.83 (br, 1H),4.69-4.62 (m, 2H), 3.36-2.91 (m, 5H), 2.82-2.65 (m, 2H), 1.53 (d, 2H),1.44 (s, 9H), 1.25 (d, 1H), 1.13 (d, 3H); CI MS m/z=416[C₂₉H₃₉N₇O-Boc+H]⁺.

Example 90 Preparation of Compound 107

To compound 106 (0.10 g, 0.18 mmol) was added Et₂O (2 mL), CH₂Cl₂ (1 mL)and MeOH (1 mL). During 16 h HCl/ether (1M, 5 mL) was added whilestirring. The resulting precipitate was collected by filtration anddried in vacuo for 30 min to provide 106 as an off-white solid (60 mg,81%): ¹H NMR (300 MHz, DMSO) δ 8.48 (br, 2H), 8.15 (br, 1H), 7.67-7.27(m, 10H), 4.79 (br, 1H), 3.60-3.42 (m, 3H), 3.18-3.06 (m, 2H), 3.03-2.91(m, 2H), 1.52 (d, 2H), 1.27 (d, 6H); CI MS m/z=416 [C₂₄H₂₉N₇+H]⁺.

Example 91 Preparation of Compound 108

A stock solution of acetic anhydride was made by mixing CH₂Cl₂ (16 mL),pyridine (4 mL), and Ac₂O (0.16 mL). To this solution (5.6 mL) was addedcompound 107 (0.04 g, 0.09 mmol), followed by DMAP (few crystals). Thereaction mixture was allowed to stir at room temperature for 2 h. Thereaction mixture was diluted with CH₂Cl₂, washed with 2N HCl untilacidic, the organic layer was washed with NaHCO₃, dried over MgSO₄,filtered, and evaporated to give a white solid (16 mg). The product waspurified by column chromatography to provide 108 as a white solid (0.01g, 18%): ¹H NMR (300 MHz, CDCl₃) δ 7.58-7.43 (m, 10H), 6.60 (br, 1H),5.91 (br, 1H), 5.04 (t, 1H), 4.84 (br, 2H), 4.72-4.59 (m, 1H), 4.10-4.02(m, 1H), 3.59-3.47 (m, 2H), 1.80 (s, 3H), 1.57 (d, 6H), 1.19 (d, 3H); CIMS m/z=458 [C₂₆H₃₁N₇O+H]⁺.

Example 92 Preparation of Compound 109

Compound 61 (1.0 g, 2.18 mmol), 3-chlorophenylboronic acid (1.3 g, 8.16mmol), PPh₃ (0.3 g, 1.26 mmol), 2M Na₂CO₃ (5.0 mL), and DME (54 mL) wereadded to a three-necked round-bottomed flask. The mixture was degassedwith argon and heated to reflux for 40 min, cooled to room temperature,and then Pd₂(dba)₃ (0.08 g, 0.08 mmol) was added. The reaction mixturewas heated at reflux for 7 h. 3-Chlorophenylboronic acid (0.6 g) andPd₂(dba)₃ (0.08 g) was then added and reflux continued for 12 h. Thereaction mixture was cooled to room temperature, diluted with H₂O (50mL), and extracted with CH₂Cl₂ (3×50 mL). The combined organic phaseswere washed with H₂O (50 mL), brine (50 mL), dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography and concentrated in vacuo to obtain compound 109 (950mg, 89%): mp 178-181° C.; ¹H NMR (500 MHz, CDCl₃) δ 7.56 (s, 1H),7.42-7.54 (m, 6H), 7.26-7.35 (m, 2H), 6.08 (bs, 1H), 4.81 (bs, 2H),4.5-94.64 (m, 2H), 3.75-3.81 (m, 1H), 2.65-2.72 (m, 1H), 2.12 (d, 2H),1.88 (d, 2H), 1.53 (d, 6H), 1.18-1.27 (m, 4H); CI MS m/z=490[C₂₇H₃₂ClN₇+H]⁺.

Example 93 Preparation of Compound 110

Compound 109 (500 mg, 1.02 mmol) was dissolved in anhydrous CH₂Cl₂ (30mL), cooled with an ice-water bath, followed by the addition of DMAP(12.2 mg, 0.1 mmol), pyridine (124 μL, 1.53 mmol), and Ac₂O (106 μL,1.12 mmol). The reaction mixture was stirred for 30 min at 0° C. anice-water bath then stirred another 2 h at room temperature. Thereaction mixture was then concentrated in vacuo and the residue waspurified by column chromatography on silica gel. After removal of thesolvent, the residue was dried in vacuo to give 110 (339 mg, 63%): mp198-200° C.; ¹H NMR (500 MHz, CDCl₃) δ 7.57 (s, 1H), 7.39-7.53 (m, 6H),7.27-7.37 (m, 2H), 6.31 (bs, 1H), 5.28 (d, 1H), 4.78 (bs, 2H), 4.70 (d,1H), 4.58-4.67 (m, 1H), 3.72-3.83 (m, 1H), 2.18 (d, 2H), 2.00 (d, 2H),1.90 (s, 3H), 1.51 (d, 6H), 1.18-1.31 (m, 4H); CI MS m/z=532[C₂₉H₃₄ClN₇O+H]⁺.

Example 94 Preparation of Compound 111

Compound 61 (1.0 g, 2.18 mmol), 2-thiopheneboronic acid (1.0 g, 8.16mmol), PPh₃ (0.3 g, 1.26 mmol), 2M Na₂CO₃ (5.0 mL), Pd₂(dba)₃ (0.08 g,0.08 mmol), and DME (54 mL) were added to a round-bottomed flask andpurged with argon. The reaction mixture was heated at reflux for 24 h.2-Thiopheneboronic acid (0.5 g), Pd₂(dba)₃ (0.1 g), and 2M Na₂CO₃ (2 mL)were added and heated to reflux for another 24 h. The reaction mixturewas cooled to room temperature, diluted with H₂O (50 mL) and extractedwith CH₂Cl₂ (3×50 mL). The organic phase was washed with H₂O (50 mL) andbrine (50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo.The residue was repeatedly chromatographed on silica gel to obtain 111(574 mg, 59%): mp 109-110° C.; ¹H NMR (500 MHz, CDCl₃) δ 7.56 (d, 2H),7.54 (s, 1H), 7.46 (d, 2H), 7.24-7.37 (m, 2H), 7.06 (t, 1H), 6.04 (bs,1H), 4.78 (bs, 2H), 4.59-4.69 (m, 2H), 3.75-3.81 (m, 1H), 2.67-2.74 (m,1H), 2.14 (d, 2H), 1.87 (d, 2H), 1.52 (d, 6H), 1.17-1.29 (m, 4H); CI MSm/z=462 [C₂₅H₃₁N₇S+H]⁺.

Example 95 Preparation of Compound 112

Compound 111 (410.0 mg, 0.89 mmol) was dissolved in anhydrous CH₂Cl₂ (30mL) and purged with N₂ and cooled with an ice-water bath. Pyridine (108mg, 1.34 mmol) and DMAP (10.9 mg, 0.09 mmol) followed by Ac₂O (92 μL,0.98 mmol) were added slowly. The reaction mixture was stirred for 30min in an ice-water bath followed by 2 h at room temperature. Thereaction mixture was concentrated in vacuo. The residue waschromatographed on silica gel to give 112 (325 mg, 73%): mp 237-244° C.;¹H NMR (500 MHz, CDCl₃) δ 7.54 (d, 2H), 7.50 (s, 1H), 7.36 (d, 2H),7.24-7.37 (m, 2H), 7.08 (t, 1H), 6.06 (bs, 1H), 5.34 (s, 1H), 4.78 (bs,2H), 4.58-4.70 (m, 2H), 3.78 (bs, 2H), 2.17 (d, 2H), 2.04 (d, 2H), 1.96(s, 3H), 1.56 (d, 6H), 1.18-1.32 (m, 4H); CI MS m/z=504 [C₂₇H₃₃N₇OS+H]⁺.

Example 96 Preparation of Compound 113

Compound 12 (600 mg, 1.30 mmol) was dissolved in anhydrous CH₂Cl₂ (40mL), purged with N₂, and cooled to 0° C. followed by an addition of DMAP(15.9 mg, 0.13 mmol), pyridine (165.3 mg, 1.95 mmol), and Ac₂O (135 mg,1.43 mmol). The mixture was stirred 30 min at 0° C. then 2 h at roomtemperature. The reaction mixture was concentrated in vacuo. The residuewas chromatographed on silica gel to give 113 (495 mg, 76%): mp 248-253°C.; ¹H NMR (500 MHz, CDCl₃) δ 7.54 (d, 2H), 7.46 (s, 1H), 7.35-7.41 (m,5H), 6.13 (bs, 1H), 5.28 (d, 1H), 4.78 (br, 2H), 4.61-4.63 (m, 2H), 3.75(bs, 2H), 2.14 (d, 2H), 1.97 (d, 2H), 1.95 (s, 3H), 1.52 (d, 6H),1.15-1.37 (m, 4H); CI MS m/z=504 [C₂₇H₃₃N₇OS+H]⁺.

Example 97 Preparation of Compound 114

To compound 61 (1.0 g, 2.18 mmol) was added PPh₃ (330 mg, 1.26 mmol), 2MNa₂CO₃ (5 mL), DME (54 mL), and 4-carboxyphenylboronic acid (1.0 g, 6.03mmol). The mixture was purged with N₂ for 45 min then Pd₂(dba)₃ (366 mg,0.4 mmol) was added and the mixture was heated at reflux for 3 d. Thereaction mixture was diluted with H₂O (100 mL). The aqueous layer wasseparated, and washed with CH₂Cl₂ (3×40 mL). The aqueous layer wasadjusted the pH to 5.8 by using 1N HCl. Some precipitate appeared. Themixture was stored in a freezer overnight. The precipitate was collectedand dried to obtain 114 (450 mg, 41%): mp 246-249° C. (dec.); ¹H NMR(500 MHz, CD₃OD+NaOD) δ 7.84 (s, 2H), 7.64 (s, 1H), 7.54-7.63 (m, 4H),7.39 (s, 2H), 6.08 (bs, 1H), 4.85 (bs, 2H), 4.73 (s, 1H), 3.76 (m, 1H),2.74 (m, 1H), 1.99 (s, 2H), 1.88 (s, 2H), 1.63 (d, 6H), 1.21-1.36 (m,4H); CI MS m/z=500 [C₂₈H₃₃N₇O₂+H]⁺.

Example 98 Preparation of Compound 115

To a cooled MeOH (20 mL) solution was slowly added TMSCl (253 μL, 2.0mmol). The solution was stirred 20 min, followed by the addition of 114(100 mg, 0.2 mmol). The reaction mixture was stirred at room temperaturefor 24 h. The reaction mixture was cooled with an ice-water bath thenEt₃N (557 mL) was added. The mixture was concentrated in vacuo, toprovide the crude product, which was washed with water (2×20 mL). Theresidue was purified by chromatography on a silica gel. After removal ofthe solvent and drying in vacuo, the residue was dissolved in MeOH (5mL), followed by the addition of ether (10 mL). The precipitate wascollected and dried to provide 115 (75 mg, 73%): mp194-197° C.; ¹H NMR(500 MHz, CD₃OD) δ 8.07 (d, 2H), 7.80 (s, 1H), 7.72 (d, 2H), 7.63 (d,2H), 7.46 (d, 2H), 4.63-4.79 (m, 1H), 3.91 (s, 3H), 3.65-3.77 (m, 1H),3.07 (bs, 1H), 2.12 (d, 2H), 2.01 (d, 2H), 1.55 (d, 6H), 1.29-1.49 (m,4H); API MS m/z=514 [C₂₉H₃₅N₇O₂+H]⁺.

Example 99 Preparation of Compound 117

To a suspension of compound 114 (250 mg, 0.50 mmol), pyridine (60 μL,0.75 mmol), and DMAP (6.1 mg, 0.05 mmol) in H₂O-dioxane (2:1, 40 mL) wasadded Ac₂O (57 μL, 0.60 mmol). After stirring 4 h at room temperature,K₂CO₃ (100 mg) was added followed by additional Ac₂O (100 μL). Thereaction mixture was stirred 2 h at room temperature. Water (50 mL) wasadded and the pH was adjusted to 5. The precipitate was collected,washed with water and ether, and dried in vacuo. The precipitate (200mg) was added to a solution of TMSCI (500 μL, 3.94 mmol) in MeOH (25mL). The reaction mixture was stirred 24 h at room temperature. Themixture was concentrated in vacuo. The product was purified by silicalgel chromatography to provide 117 (145 mg, 52%): mp 247-250° C.; ¹H NMR(500 MHz, CDCl₃) δ 8.09 (d, 2H), 7.64 (d, 2H), 7.58 (d, 2H), 7.49 (s,1H), 7.45 (d, 2H), 5.91 (bs, 1H), 5.18 (d, 1H), 4.83 (bs, 2H), 4.61-4.68(m, 2H), 3.93 (s, 3H), 3.67-3.78 (m, 2H), 3.07 (bs, 1H), 2.16 (d, 2H),2.02 (d, 2H), 1.95 (s, 3H), 1.54 (d, 6H), 1.23-1.32 (m, 4H); API MSm/z=556 [C₃₁H₃₇N₇O₃+H]⁺.

Example 100 Preparation of Compound 116

To a solution of compound 117 (90 mg, 0.16 mmol) in MeOH-H₂O (6:1, 23mL) was added KOH (11 mg, 0.19 mmol) in 5 mL MeOH. The reaction mixturewas refluxed for 24 h. After removal of the solvent the residue wasdissolved in 15 mL of water and washed with CH₂Cl₂. The aqueous layerwas separated and adjusted pH to 4.5 by using 1N HCl. The precipitatewas collected and dried to obtain 116 (60 mg, 68%): mp 344-347° C.; ¹HNMR (500 MHz, DMSO-d₆) δ 11.21 (bs, 1H), 8.14 (d, 2H), 7.64-7.88 (m,6H), 7.47 (d, 2H), 6.06 (bs, 1H), 5.18 (d, 1H), 4.85 (bs, 2H), 4.51-4.66(m, 1H), 3.62 (bs, 1H), 3.46 (bs, 1H), 1.89 (bs, 2H), 1.77 (bs, 5H),1.95 (s, 3H), 1.47 (d, 6H), 1.23-1.36 (m, 4H); API MS m/z=542[C₃₀H₃₅N₇O₃+H]⁺.

Example 101 Preparation of Compound 118

Compound 61 (1.0 g, 2.18 mmol), 3-carboxyphenylboronic acid (1.0 g, 6.03mmol), 2N Na₂CO₃ (5 mL), and DME/EtOH (50 mL) were mixed together anddegassed with N₂ for 1 h. Pd₂(dba)₃ (366.0 mg, 0.4 mmol) and PPh₃ (330.0mg, 1.26 mmol) were added and the reaction mixture was heated to refluxfor 48 h. The reaction mixture was cooled to room temperature, dilutedwith CH₂Cl₂ (50 mL), and extracted with aqueous 5% Na₂CO₃ (3×30 mL). Thecombined washes were extracted with CH₂Cl₂ (3×30 mL) and ether (40 mL).The aqueous phase was neutralized to a pH of 5.8 using 1N HCl and keptin a freezer for 1 h. The precipitate was collected, suspended in MeOH(30 mL) and the insolubles were removed by filtration. To the MeOHsolution was added ether (20 mL) to precipitate the product. The whitesolid was collected and dried in vacuo to offer 118 (65 mg, 6%): mp205-208° C.; ¹H NMR (500 MHz, CD₃OD+NaOD) δ 8.17 (s, 1H), 7.88 (d, 1H),7.80 (s, 1H), 7.56-7.63 (m, 3H), 7.35-7.41 (m, 3H), 6.08 (bs, 1H), 4.80(bs, 2H), 4.59-4.75 (m, 1H), 3.72-3.82 (m, 1H), 2.89-3.01 (m, 1H),1.90-1.99 (m, 4H), 1.51 (d, 6H), 1.29-1.40 (m, 2H), 1.12-1.23 (m, 2H);API MS m/z=500 [C₂₈H₃₃N₇O₂+H]⁺.

Example 102 Preparation of Compound 119

3-Thiopheneboronic acid (4.5 g, 35.2 mmol) and 6-chloronicotinamide (5.0g, 32.0 mmol) were dissolved in DMA (150 mL), followed by the additionof 2N Na₂CO₃ (23 mL). N₂ gas was passed through the mixture for 1 h.Pd(PPh₃)₄ (0.74 g, 0.64 mmol) was added and the reaction mixture washeated to reflux for 24 h. The reaction mixture was cooled to roomtemperature and poured into an ice-water (1 L) and stirred for 10 min.The precipitate was collected and washed with acetone. The collectedsolid was suspended in EtOAc (150 mL) and heated to reflux for 5 min.The solid was filtered and collected. After drying in vacuo, 119 (4.5 g,69%) was obtained: ¹H NMR (500 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.34 (s,1H), 8.28 (d, 1H), 8.20 (bs, 1H), 7.99 (d, 1H), 7.81 (d, 1H), 7.71 (d,1H), 7.60 (bs, 1H).

Example 103 Preparation of Compound 120

To compound 119 (4.08 g, 20.0 mmol) suspended in THF (50 mL), was added1M BH₃-THF (164 mL). The mixture was heated to reflux for 9 h. Themixture was cooled with an ice-water bath and adjusted to a pH of 1-2,and stirred for 1 h at room temperature. The pH was adjusted to 9-10 (2NNaOH) and extracted with EtOAc (3×50 mL). The combined organic phaseswere washed with H₂O (50 mL), brine (50 mL), and dried over Na₂SO₄.After filtration and removal of the solvent, the residue was dissolvedin EtOH (50 mL), followed by the addition of 1M HCl/ether (20 mL). Themixture was concentrated to dryness to provide 120 (2.03 g, 45%): ¹H NMR(500 MHz, CD₃OD) δ 8.93 (s, 1H), 8.61 (d, 1H), 8.51 (s, 1H), 8.43 (d,1H), 7.81 (d, 1H), 7.70 (d, 1H), 3.30 (t, 2H).

Example 104 Preparation of Compound 121

Compound 120 (2 g, 8.82 mmol), 2,6-dichloropurine (1.5 g, 8.01 mmol),EtOH (50 mL), and (i-Pr)₂NEt (3.8 mL, 22 mmol) were heated at reflux for16 h. The reaction mixture was then cooled with an ice-water bath. Theprecipitate was collected and washed with EtOH, H₂O, and ether. Theprecipitate was dried in vacuo to obtain 121 (0.84 g, 31%): ¹H NMR (500MHz, DMSO-d₆) δ 11.02 (bs, 1H), 8.76 (bs, 1H), 8.63 (s, 1H), 8.07 (bs,2H), 7.79 (bs, 2H), 7.71 (d, 1H), 7.64 (d, 1H), 4.68 (bs, 2H).

Example 105 Preparation of Compound 122

Compound 121 (950 mg, 2.77 mmol) was dissolved in DMSO (50 mL), and thenK₂CO₃ (2.07 g, 15.0 mmol) was added, followed by the addition of2-iodopropane (830 μL, 8.31 mmol). The reaction mixture then was stirredat room temperature overnight. The reaction mixture was poured into anice-water bath (400 mL), stirred for 10 min, and extracted with EtOAc(4×50 mL). The combined organic phases were washed with H₂O (40 mL),brine (40 mL), and dried over MgSO₄. After filtration and removal of thesolvent, the residue was dissolved in hot EtOAc (40 mL), followed by theaddition of hexanes (80 mL). The precipitate was collected and dried invacuo to obtain 122 (798 mg, 90%): ¹H NMR (500 MHz, CDCl₃) δ 8.64 (s,1H), 7.83 (s, 1H), 7.70-7.79 (m, 2H), 7.60 (d, 1H), 7.55 (d, 1H), 7.36(d, 1H), 6.11 (bs, 1H), 4.77-4.96 (m, 3H), 1.53 (d, 6H).

Example 106 Preparation of Compound 123

Compound 122 (780.0 mg, 2.03 mmol), trans-1,4-diaminocyclohexane (2.3 g,20.3 mmol), and EtOH (4 mL) were heated in a sealed tube to 150° C. for20 h. The reaction mixture was poured into ice-water (150 mL) andstirred for 10 min. The resulting precipitate was washed with H₂O (2×20mL) and dried. The solid was chromatographed on a silica gel column.After removal of the solvent and drying in vacuo, 123 (765 mg) wasobtained: mp 78-81° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.63 (s, 1H), 7.87 (s,1H), 7.72 (d, 1H), 7.64 (d, 1H), 7.55 (d, 1H), 7.04-7.09 (m, 1H), 6.92(s, 1H), 5.95 (bs, 1H), 4.64 (bs, 2H), 4.33-4.45 (m, 2H), 3.74-3.77 (m,1H), 2.67-2.76 (m, 1H), 2.13 (d, 2H), 1.90 (d, 2H), 1.63 (bs, 2H), 1.54(d, 6H), 1.19-1.30(m, 4H); ¹³C NMR(CDCl₃) δ 159.1, 155.0, 152.7, 151.3,149.3, 143.3, 142.3, 136.2, 134.8, 133.4, 126.4, 126.4, 123.5, 120.2,114.8, 50.4, 50.3, 46.5, 42.0, 35.7, 32.3, 22.8; API MS m/z=463[C₂₄H₃₀N₈S+H]⁺.

Example 107 Preparation of Compound 124

To an ice-cold solution of compound 123 (420 mg, 0.91 mmol) in CH₂Cl₂(20 mL) was added pyridine (110 μL, 1.4 mmol), DMAP (11.0 mg, 0.09 mmol)and Ac₂O (94.2 μL, 1 mmol). The reaction mixture was stirred for 30 minat 0° C., followed by 2 h at room temperature. After removal of thesolvent, the residue was chromatographed on a silica gel column. Theresulting solid was recrystallized with EtOAc/MeOH and dried in vacuo togive 124 (350 mg, 79%): mp 249-252° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.61(s, 1H), 7.85 (s, 1H), 7.70 (d, 1H), 7.62 (d, 1H), 7.53 (d, 1H), 7.48(s, 1H), 7.38 (d, 1H), 6.00 (bs, 1H), 5.25 (d, 1H), 4.77 (bs, 2H),4.53-4.72 (m, 2H), 3.68-3.77 (m, 2H), 2.10 (d, 2H), 2.00 (d, 2H), 1.94(s, 3H), 1.52 (d, 6H), 1.17-1.28 (m, 4H); ¹³C NMR (CDCl₃) δ 169.4,159.0, 155.0, 152.8, 149.2, 142.8, 142.3, 136.1, 134.9, 133.4, 126.5,126.4, 123.5, 120.2, 114.9, 50.1, 48.3, 46.5, 42.2, 32.2, 32.1, 22.8;API MS m/z=505 [C₂₆H₃₂N₈OS+H]⁺.

Example 108 Alternative Preparation of Compound 71

To a solution of 4-phenylbenzoic acid (5.46 g, 27.6 mmol) in methylenechloride (66 mL) was added 2 drops of DMF and oxalyl chloride (2.80 mL,30.3 mmol). The reaction mixture was stirred overnight and added to astirred solution of ice and ammonium hydroxide. The resultingprecipitate was filtered, washed with methylene chloride, and trituratedwith water. The product was collected by filtration and dried in vacuoto yield 4-phenylbenzamide (3.88 g, 71%).

Under a nitrogen atmosphere, 4-phenylbenzamide (2.01 g, 10.2 mmol) wasdissolved in THF (50 mL) and heated to reflux. To the mixture was addeddropwise 1 M borane in THF (80.0 mL, 80.0 mmol). After refluxing for 18h, the reaction mixture was cooled to room temperature and treated with1 N HCl (40 mL). The solution was made basic via addition of 3 N NaOH(60 mL) and extracted with ethyl acetate (3×370 mL). The extract waswashed with brine and dried over sodium sulfate. Concentration yielded4-phenylbenzyl amine as a white solid (1.73 g, 93%).

4-Phenylbenzyl amine (1.73 g, 10.1 mmol) and 2,6-dichloropurine (1.94 g,10.1 mmol) was dissolved in water (110 mL). To the solution was addedN,N-diisopropylethylamine (3.54 mL, 20.2 mmol). The reaction mixture washeated to reflux for 5 h and cooled to room temperature. A precipitatewas collected by filtration. The solid was washed with water and ethanoland dried to yield 71 (2.35 g, 69%): ¹H NMR (300 MHz, (CD₃)₂SO) δ 8.69(brs, 1H), 8.15 (s, 1H), 7.57-7.68 (m, 4H), 7.30-7.50 (m, 5H), 4.71 (d,2H).

Example 109 Preparation of Compound 126

To a stirred solution of 3-iodobenzylamine (5.00 g, 21.4 mmol) in water(100 mL) was added 2,6-dichloropurine (4.04 g, 21.4 mmol) andN,N-diisopropylethylamine (7.47 mL, 42.5 mmol). The mixture was refluxedfor 5 h and stored at room temperature overnight. The resultingsuspension was filtered. The filter cake was triturated with water (3×25mL) and ethanol (2×15 mL) and dried under high vacuum to yield 126 (7.49g, 91%): ¹H NMR (300 MHz, (CD₃)₂SO) δ 8.50-8.80 (brs, 1H), 8.17 (s, 1H),7.75 (s, 1H), 7.61 (d, 1H), 7.37 (d, 1H), 7.14 (t, 1H), 5.14 (brs, 1H),4.61 (d, 2H).

Example 110 Preparation of Compound 127

The purine derivative 126 (7.00 g, 18.2 mmol) was dissolved indimethylsulfoxide (120 mL). To this stirred solution was added potassiumcarbonate (20.0 g, 145 mmol) and 2-iodopropane (7.28 mL, 72.8 mmol). Thereaction mixture was stirred under a nitrogen atmosphere for 20 h beforebeing poured into stirred water (600 mL). After 10 min, the resultingmixture was extracted with ethyl acetate (4×95 mL). The combined organiclayers were washed with water (25 mL) and brine (3×25 mL), dried oversodium sulfate, and concentrated in vacuo. The resulting material waspurified by recrystallization from ethyl acetate in hexanes to yield 127(7.51 g, 97%): mp 147-152° C.; ¹H NMR (300 MHz, (CD₃)₂SO) δ 8.84 (m,1H), 8.31 (s, 1H), 7.74 (s, 1H), 7.60 (d, 1H), 7.36 (d, 1H), 7.13 (t,1H), 4.51-4.75 (m, 3H), 1.50 (d, 6H); API MS m/z=429 [C₁₅H₁₅ClIN₅H]⁺.

Example 111 Preparation of Compound 128

In a sealed tube, 127 (2.57 g, 6.00 mmol), trans-1,4-diaminocyclohexane(6.85 g, 60.0 mmol), and ethanol (10 mL) were combined. The reactionmixture was heated to 160° C. for 24 h. After cooling to roomtemperature, the mixture was filtered. The filtrate was concentrated anddiluted with ethyl acetate (250 mL). The organic solution was washedwith water (250 mL) and saturated sodium bicarbonate solution (2×250mL). The organic layer was dried over sodium sulfate, filtered, andconcentrated. A portion of the resulting crude product was purified viasilica gel chromatography to yield 128 (181 mg): ¹H NMR (300 MHz,(CD₃)₂SO) δ 7.87 (brs, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.55 (d, 1H),7.35 (d, 1H), 7.09 (t, 1H), 6.06 (d, 1H), 4.43-4.70 (m, 3H), 3.58 (brs,1H), 1.66-1.94 (m, 4H), 1.46 (d, 6H), 1.00-1.30 (m, 4H); ESI MS m/z=506[C₂₁H₂₈IN₇+H]⁺.

Example 112 Preparation of Compound 129

The amine 127 (6.06 g, 6.00 mmol) was dissolved in a mixture oftetrahydofuran (45 mL) and water (15 mL). To this stirred mixture wereadded sodium bicarbonate (2.02 g, 24.0 mmol) anddi-tert-butyldicarbonate (2.90 g, 13.3 mmol). After 3.5 h, the solutionwas extracted with methylene chloride (3×75 mL). The organic extractswere combined, washed with brine (225 mL), and dried over sodiumsulfate. The organic liquid was concentrated and the resulting materialwas purified via silica gel chromatography (33:67 to 50:50 to 60:40ethyl acetate/hexanes) to yield 129 (4.94 g, 68%): ¹H NMR (300 MHz,CDCl₃) δ 7.72 (s, 1H), 7.58 (d, 1H), 7.46 (s, 1H), 7.30 (d, 1H), 7.02(t, 1H), 4.50-4.76 (m, 4H), 4.40 (m, 1H), 3.70 (brs, 1H), 3.43 (brs,1H), 1.90-2.20 (m, 4H), 1.51 (d, 6H), 1.45 (s, 9H), 1.13-1.35 (m, 4H);API MS m/z=607 [C₂₆H₃₆IN₇O₂+H]⁺.

Example 113 Preparation of Compound 130

To a stirred solution of 129 (1.00 g, 1.65 mmol) in ethylene glycoldimethyl ether (40 mL) was added 3-thiopheneboronic acid,triphenylphosphine (250 mg, 0.950 mmol), and 2 M sodium carbonatesolution (3.8 mL). The mixture was purged with nitrogen for 10 min andtris(dibenzylideneacetone)dipalladium(0) (64.0 mg, 0.060 mmol) wasadded. After refluxing overnight under nitrogen, the reaction mixturewas cooled to room temperature and diluted with water (100 mL). Theresulting solution was extracted with methylene chloride (3×50 mL). Theorganic extracts were combined, washed with brine (30 mL), and driedover sodium sulfate. The organic liquid was filtered and concentrated invacuo. Purification via silica gel chromatography (50:50 ethylacetate/hexanes) yielded 130 (0.87 g, 94%): ¹H NMR (300 MHz, CDCl₃) δ7.23-7.30 (m, 8H), 6.02 (brs, 1H), 4.78 (d, 2H), 4.53-4.68 (m, 1H), 4.32(m, 1H), 3.70 (m, 1H), 3.28-3.55 (m, 1H), 1.80-2.19 (m, 4H), 1.53 (d,6H), 1.45 (s, 9H), 1.05-1.32 (m, 4H); ESI MS m/z=562 [C₃₀H₃₉N₇O₂S+H]⁺.

Example 114 Preparation of Compound 131

To a solution of 130 in EtOAc was added 1 N HCl. After concentration ofthe solution, isolate 131 (658 mg, 91%): mp 211-216° C.; ¹H NMR (300MHz, CD₃OD) δ 8.40 (brs, 1H), 7.25-7.85 (m, 7H), 4.60-5.10 (m, 5H), 3.91(m, 1H), 3.16 (m, 1H), 1.94-2.33 (m, 4H), 1.32-1.79 (m, 10H); ESI MSm/z=462 [C₂₅H₃₁N₇S+H]⁺.

Example 115 Preparation of Compound 132

Following procedures outlined above for acetylation, prepared 132 from131 (352 mg, 80%): mp 209-211° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.27-7.67(m, 8H), 6.25 (brs, 1H), 5.19 (d, 1H), 4.79 (d, 2H), 4.52-4.67 (m, 2H),3.69 (m, 2H), 2.09 (m, 2H), 1.88-1.98 (m, 5H), 1.50 (d, 6H), 1.06-1.33(m, 4H); ESI MS m/z=504 [C₂₇H₃₃N₇OS+H]⁺.

Example 116 Preparation of Compound 133

Following general procedures outilined above for Suzuki Couplingreaction, prepared 133 from 129 (0.61 g, 67%): ¹H NMR (300 MHz, CDCl₃) δ7.30-7.62 (m, 10H) 6.00 (brs, 1H), 4.83 (d, 2H), 4.54-4.70 (m, 2H), 4.37(m, 1H), 3.71 (m, 1H), 3.39 (m, 1H), 2.12 (m, 2H), 2.47 (m, 2H), 1.53(d, 6H), 1.45 (s, 9H), 1.19 (m, 4H); ESI MS m/z=556 [C₃₂H₄₁N₇O₂+H]⁺.

Example 117 Preparation of Compound 134

To a stirred solution of 133 (530 mg, 0.950 mmol) in methanol (3 mL) wasadded 1 N HCl in diethyl ether (9.50 mL, 9.50 mmol). After stirring for3.5 h, hydrogen chloride gas was gently bubbled through the solution.After 20 min, the solution was concentrated in vacuo. The resultingmaterial was recrystallized from methanol in ether to afford 134 inquantitative yield: ¹H NMR (300 MHz, CD₃OD) δ 8.33 (brs, 1H), 7.67 (s,1H), 7.52-7.64 (m, 3H), 7.29-7.50 (m, 5H), 4.80-5.00 (m, 4H), 4.72 (m,1H), 3.87 (m, 1H), 3.14 (m, 1H), 2.02-2.25 (m, 4H), 1.59 (d, 6H), 1.47(m, 4H); ESI MS m/z=456 [C₂₇H₃₃N₇+H]⁺.

Example 118 Preparation of Compound 135

Following procedures outlined above for acetylation, prepared 135 from134 (195 mg, 82%): mp 183-185° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.30-7.64(m, 10H), 6.19 (brs, 1H), 5.12 (d, 1H), 4.81 (d, 2H), 4.60 (m, 2H), 3.68(m, 2H), 2.09 (m, 2H), 1.86-1.99 (m, 5H), 1.51 (d, 5H), 1.04-1.32 (m,4H); ESI MS m/z=498 [C₂₉H₃₅N₇O+H]⁺.

Example 119 Preparation of Compound 136

To a mixture of 71 (2.00 g, 5.96 mmol) in dimethylsulfoxide (44 mL) wasadded potassium carbonate (6.56 g, 47.7 mmol) and iodoethane (2.00 mL,24.4 mmol). After stirring overnight, the reaction mixture was pouredinto a stirred solution of water (300 mL). After 2 d, it was filtered.The filtrate was extracted with ethyl acetate (2×180 mL). The organicextracts were combined and washed with brine (150 mL). The organic layerwas dried over magnesium sulfate. Concentration afforded 136 (1.90 g,88%).

Example 120 Preparation of Compound 137

In a sealed tube, 136 (0.60 g, 1.66 mmol), trans-1,4-diaminocyclohexane(1.93 g, 16.8 mmol), and potassium iodide (10 mg), were dissolved inethanol (18 mL). The mixture was heated to 160° C. After 4 d, themixture was cooled to room temperature and filtered. The filtrate wasdissolved in ethyl acetate and washed with water (2×100 mL) and brine(100 mL). The organic layer was dried over magnesium sulfate, filtered,and concentrated. The material was purified by silica gel chromatographyand recrystallization from ethanol in hexanes (1:10) to yield 137 (886mg, 41%): mp 175-182° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.30-7.75 (m, 10H),4.55-4.95 (m, 4H), 4.10 (q, 2H), 3.78 (m, 1H), 2.99 (m, 1H), 2.11 (d,2H), 1.99 (d, 2H), 1.44 (m, 3H), 1.31 (m 4H); ESI MS m/z=442[C₂₆H₃₁N₇+H]⁺.

Example 121 Preparation of Compound 138

Compound 71 (2.02 g, 6.02 mmol), iodomethane (1.50 mL, 24.4 mmol), andpotassium carbonate were dissolved in dimethylsulfoxide (44 mL) andstirred overnight. The reaction mixture was poured into 150 mL ofstirring water. The organic and aqueous layers were separated. Theorganic layer was washed with brine (3×100 mL) and dried over magnesiumsulfate. The solids were removed by filtration and the solution wasconcentrated in vacuo to afford 138 (1.93 g, 93%).

Example 122 Preparation of Compound 139

In a sealed tube, 138 (1.80 g, 5.15 mmol) andtrans-1,4-diaminocyclohexane (5.90 g, 51.7 mmol) were dissolved inethanol (85 mL). The mixture was heated to 140° C. After heatingovernight, the reaction mixture was cooled to room temperature andconcentrated. The resulting solid was dissolved in ethyl acetate (160mL) and washed with water (160 mL) and brine (2×100 mL). The organiclayer was dried over magnesium sulfate and filtered. Concentrationafforded a solid, which was purified by silica gel chromatography andrecrystallization from ethanol in hexanes (1:20) and ethyl acetate inhexanes to yield 139 (850 mg, 38%): mp 182-184° C.; ¹H NMR (500 MHz,CD₃OD) δ 7.25-7.70 (m, 10H), 4.64-4.90 (m, 4H), 3.75 (m, 1H), 3.65 (s,3H), 2.68 (m, 1H), 2.05 (m, 2H), 1.88 (m, 2H), 1.25 (m, 4H); ESI MSm/z=428 [C₂₅H₂₉N₇+H]⁺.

Example 123 Preparation of Compound 140

The HCl salt of 139 (86.7 mg, 0.162 mmol) was suspended in methylenechloride (20 mL). The suspension was immersed in an ice bath whiletriethylamine (0.16 mL, 1.12 mmol) and a catalytic amount of DMAP wereadded. Acetyl chloride (0.04 mL, 0.560 mmol) was added to the mixture.The reaction was quenched by the addition of 5% aqueous NaHCO₃ solution(50 mL). The aqueous layer was extracted with methylene chloride (2×50mL). The extracts were washed with brine (100 mL), dried over magnesiumsulfate, filtered, and concentrated. The resulting solid material wasdried in vacuo. Purification by silica gel chromatography andrecrystallization from ethyl acetate in hexanes (5:60) afforded 140 (6.4mg, 8%): ¹H NMR (300 MHz, CD₃OD) δ 7.50-7.68 (m, 5H), 7.25-7.47 (m, 5H),5.22 (m, 3H), 4.20-5.05 (m, 2H), 3.75 (m, 1H), 3.65 (s, 3H), 3.35-3.47(m, 1H), 2.78 (m, 1H), 1.95-2.16 (m, 2H), 1.80-1.95 (m, 2H), 1.17-1.40(m, 4H).

Example 124 Preparation of Compound 144

Compound 71 (2.03 g, 5.96 mmol), 1-iodopropane (2.25 mL, 24.4 mmol), andpotassium carbonate (6.61 g, 47.7 mmol) were dissolved indimethylsulfoxide (44 mL) and allowed to stir overnight. The reactionmixture was added to 300 mL of stirring water and stirred for 2 d. Theresulting precipitate was collected by filtration and dried in vacuo toafford 141 (2.07 g, 92%).

Example 125 Preparation of Compound 142

In a sealed tube, 141 (1.82 g, 4.81 mmol) andtrans-1,4-diaminocyclohexane (5.67 g, 49.7 mmol) were dissolved inethanol (53 mL). The mixture was heated to 140° C. for 3 d. Aftercooling to room temperature, the reaction mixture was concentrated anddissolved in ethyl acetate (100 mL). This solution was washed with water(100 mL) and brine (2×100 mL). The organic layer was dried overmagnesium sulfate, filtered, and concentrated. The product was purifiedby silica gel chromatography and recrystallizations from ethanol inhexanes (1:20) to yield 142 (523 mg, 24%): mp 133-138° C.; ¹H NMR (500MHz, CD₃OD) δ 7.25-7.70 (m, 10H), 4.65-4.85 (m, 4H), 4.02 (t, 2H), 3.76(m, 1H), 2.85 (m, 1H), 2.08 (d, 2H), 1.94 (d, 2H), 1.86 (q, 2H),1.20-1.42 (m, 4H), 0.93 (t, 3H); ESI MS m/z=456 [C₂₇H₃₃N₇+H]⁺.

Example 126 Preparation of Compound 143

Compound 71 (2.01 g, 5.98 mmol), iodocyclopentane (2.80 mL, 24.2 mmol),and potassium carbonate (6.75 g, 48.9 mmol) were dissolved indimethylsulfoxide (44 mL) and allowed to stir under nitrogen overnight.The reaction mixture was added to 150 mL of stirring water and dilutedwith 150 mL ethyl acetate. The organic and aqueous phases wereseparated. The organic phase was washed with brine (3×100 mL) and driedover magnesium sulfate. After filtering, the organic liquid wasconcentrated and the resulting solid was dried in vacuo to afford 143(1.29 g, 55%).

Example 127 Preparation of Compound 144

In a sealed tube, 143 (304 mg, 0.749 mmol) andtrans-1,4-diaminocyclohexane (891 mg, 7.80 mmol) were dissolved inethanol (10 mL). The mixture was heated to 140° C. for 4 d. Aftercooling to room temperature, the reaction mixture was diluted with ethylacetate (160 mL). This solution was washed with water (160 mL) and brine(2×100 mL). The organic layer was dried over magnesium sulfate,filtered, and concentrated. The material was purified by silica gelchromatography and recrystallizations from ethanol in hexanes (1:20) toyield 144 (299 mg, 19%): mp 144-146° C.; ¹H NMR (500 MHz, CD₃OD) δ7.28-7.75 (m, 10H), 4.68-4.85 (m, 4H), 3.75 (m, 1H), 2.82 (m, 1H),1.70-2.25 (m, 13H), 1.20-1.43 (m, 4H); ESI MS m/z=482 [C₂₉H₃₅N₇+H]⁺.

Example 128 Preparation of Compound 145

Compound 71 (2.01 g, 5.98 mmol), allylbromide (2.10 mL, 24.4 mmol), andpotassium carbonate (6.61 g, 47.8 mmol) were dissolved indimethylsulfoxide (44 mL) and stirred overnight. The reaction mixturewas added to 150 mL of stirring water and diluted with 150 mL ethylacetate. The organic and aqueous phases were separated. The organicphase was washed with brine (3×100 mL), dried over magnesium sulfate,filtered, and concentrated. The resulting solid was dried in vacuo toafford 145 (1.98 g, 88%).

Example 129 Preparation of Compound 146

In a sealed tube, 145 (1.99 mg, 5.29 mmol), trans-1,4-diaminocyclohexane(6.21 g, 54.3 mmol), and 2,6-di-tert-butylphenol (1.13 g, 5.48 mmol)were dissolved in ethanol (60 mL). The mixture was heated to 140° C. for4 d. After cooling to room temperature, the reaction was concentratedand diluted with ethyl acetate (175 mL). This organic solution waswashed with water (175 mL) and brine (2×100 mL) and concentrated. Theproduct was purified by silica gel chromatography and recrystallizationsfrom ethanol in hexanes (1:20) to yield 146 (432 mg, 18%): mp 111-114°C.; ¹H NMR (300 MHz, CD₃OD) δ 7.25-7.72 (m, 10H), 5.95-6.10 (m, 1H),5.21 (d, 1H), 5.10 (d, 1H), 4.82 (m, 2H), 4.77 (s, 2H), 4.67 (d, 2H),3.75 (m, 1H), 2.87 (m, 1H), 2.07 (d, 2H), 1.92 (d, 2H), 1.15-1.47 (m,4H); ESI MS m/z=454 [C₂₇H₃₁N₇+H]⁺.

Example 130 Preparation of Compound 147

Compound 71 (2.07 g, 6.17 mmol), 2-iodobutane (3.10 mL, 26.9 mmol), andpotassium carbonate (6.78 g, 49.1 mmol) were dissolved indimethylsulfoxide (44 mL) and allowed to stir under nitrogen overnight.The reaction mixture was diluted with ethyl acetate (300 mL). Theorganic material was washed with water (200 mL) and brine (300 mL) anddried over magnesium sulfate. After filtration, the material wasconcentrated and the resulting solid was dried in vacuo to afford 147(1.29 g, 55%).

Example 131 Preparation of Compound 148

In a sealed tube, 147 (1.29 g, 3.30 mmol) andtrans-1,4-diaminocyclohexane (3.80 g, 33.2 mmol) were dissolved inethanol (70 mL). The mixture was heated to 140° C. After 4 d, thereaction was cooled to room temperature, concentrated, and dissolved inethyl acetate (160 mL). This solution was washed with water (160 mL) andbrine (2×100 mL) and dried over magnesium sulfate. The organic liquidwas filtered and concentrated. The resulting solid was dried in vacuoand purified by silica gel chromatography and recrystallizations fromethanol in hexanes (1:40) to yield 148 (229 mg, 15%): mp 146-150° C.; ¹HNMR (500 MHz, CD₃OD) δ 7.70 (s, 1H), 7.25-7.60 (m, 9H), 4.65-4.90 (m,4H), 4.37 (m, 1H), 3.74 (m, 1H), 2.86 (m, 1H), 1.82-2.15 (m, 6H), 1.50(d, 3H), 1.20-1.43 (m, 4H), 0.87 (t, 3H).

Example 132 Preparation of Compound 149

To a solution of 61 (0.90 g, 1.96 mmol) in ethylene glycol dimethylether (54 mL), were added 3,5-dimethylphenylboronic acid (0.59 g, 3.93mmol), triphenylphosphine (0.26 g, 0.99 mmol), and 2 M sodium carbonatesolution (10 mL). The solution was refluxed for 20 min and cooled toroom temperature. Tris(dibenzylideneacetone)dipalladium(0) (0.66 g,0.072 mmol) was added and the reaction returned to reflux. Afterrefluxing overnight, the reaction mixture was cooled to room temperatureand another 100 mg 3,5-dimethylphenylboronic acid were added. Afterrefluxing for another 5 h, the reaction was quenched with 50 mL water.The aqueous solution was extracted with methylene chloride (3×50 mL).The extracts were combined and washed with water (50 mL) and brine (50mL). The organic solution was dried over sodium sulfate, filtered, andconcentrated. The product was purified by silica gel chromatography toyield 149: mp 86-90° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.58 (m, 5H),7.20 (s, 2H), 6.97 (s, 1H), 5.93 (brs, 1H), 4.54-4.90 (m, 4H), 3.66-3.85(m, 1H), 2.70 (m, 1H), 2.37 (s, 6H), 2.05-2.20 (m, 4H), 1.80-1.95 (m,2H), 1.54 (d, 6H), 1.10-1.35 (m, 4H); API MS m/z=484 [C₂₉H₃₇N₇+H]⁺.

Example 133 Preparation of Compound 150

To a stirred, 0° C. solution of 149 (500 mg, 0.97 mmol) in methylenechloride (20 mL), were added pyridine (120 μL), DMAP (11.8 mg, 0.097mmol), and acetic anhydride (91 μL, 0.097 mmol). After 40 min, thereaction mixture was warmed to room temperature and stirred for 3 h.Another 100 μL acetic anhydride was added. After 1 h, the solution wasconcentrated and dried in vacuo. The resulting material was purified bysilica gel chromatography (95:5:1 CH₂Cl₂/methanol/NH₄OH) to yield 150(400 mg, 80%): mp 207-210° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.46-7.56 (m,3H), 7.36-7.45 (m, 2H), 7.18 (s, 2H), 6.98 (s, 1H), 5.98 (brs, 1H), 5.27(d, 1H), 4.80 (d, 2H), 4.56-4.70 (m, 1H), 3.68-3.84 (m, 1H), 2.37 (s,6H), 1.90-2.23 (m, 7H), 1.54 (d, 6H), 1.15-1.48 (m, 4H); API MS m/z=526[C₃₁H₃₉N₇O+H]⁺.

Example 134 Preparation of Compound 152

To a solution of 149 (500 mg, 1.03 mmol) in 1,2-dichloroethane (4 mL)was added propionaldehyde (90 μL, 1.24 mmol). After stirring for 10 min,sodium triacetoxyborohydride (306 mg, 1.44 mmol) was added. The reactionmixture stirred under nitrogen for 1.5 h before being quenched withsaturated sodium bicarbonate solution (5 mL). The resulting solution wasextracted with ethyl acetate (3×7 mL). The organic extracts werecombined and dried over sodium sulfate. The organic liquid was filteredand concentrated. Purification by silica gel chromatography (90:10:1CH₂Cl₂/methanol/NH₄OH) yielded 152.

Example 135 Preparation of Compound 152.HCl

To a stirred solution of 152 (120 mg, 0.211 mmol) in ethyl acetate (10mL) was added 2 M HCl in diethyl ether (127 μL). After 20 min, thesolution was concentrated and dried in vacuo to yield the HCl salt of152: ¹H NMR (300 MHz, CD₃OD) δ 8.48 (s, 1H), 7.40-7.68 (m, 4H), 7.20 (s,2H), 6.98 (s, 1H), 4.66-5.07 (m, 3H), 3.80-4.00 (m, 1H), 2.90-3.50 (m,5H), 2.01-2.45 (m 10H), 1.36-1.90 (m, 14H), 1.02 (t, 6H); API MS m/z=568[C₃₅H₄₉N₇+H]⁺.

Example 136 Preparation of Compound 151

To a solution of 149 (302 mg, 0.624 mmol) in 1,2-dichloroethane (2.5 mL)was added propionaldehyde (36.0 μL, 0.500 mmol). After stirring for 15min under nitrogen, sodium triacetoxyborohydride (93.0 mg, 0.874 mmol)was added. After 10 min, another 93.0 mg (0.874 mmol) sodiumtriacetoxyborohydride were added. The reaction mixture stirred undernitrogen for 1.5 h before being quenched with saturated sodiumbicarbonate solution (5 mL). The resulting solution was extracted withethyl acetate (3×7 mL). The organic extracts were combined and driedover sodium sulfate. The organic liquid was filtered and concentrated.Purification by silica gel chromatography (90:10:1CH₂Cl₂/methanol/NH₄OH) yielded 151.

Example 137 Preparation of Compound 151.HCl

To a stirred solution of 151 (90.0 mg, 0.171 mmol) in ethyl acetate (8mL) was added 2 M HCl in diethyl ether (103 μL). After 20 min, thesolution was concentrated and dried in vacuo to yield the HCl salt of151: mp 280-290° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.45 (brs, 1H), 7.38-7.67(m, 4H), 7.29 (s, 2H), 6.97 (s, 1H), 4.63-5.40 (m, 4H), 3.78-3.97 (m,1H), 2.85-3.23 (m, 3H), 2.07-2.44 (m, 8H), 1.32-1.87 (m, 14H), 1.02 (t,3H); API MS m/z=526 [C₃₂H₄₃N₇+H]⁺.

Example 138 Preparation of Compound 153

To a solution of 61 (2.03 g, 4.44 mmol) in ethylene glycol dimethylether (100 mL), was added 2,5-dimethoxyphenylboronic acid (2.42 g, 13.3mmol), tris(dibenzylideneacetone)dipalladium(0) (0.135 g, 0.148 mmol),triphenylphosphine (0.581 g, 2.22 mmol), and 2 M sodium carbonatesolution (10 mL). The dispersion was refluxed overnight under nitrogen.After cooling to room temperature, the reaction mixture was diluted with100 mL water. The aqueous solution was extracted with methylene chloride(3×100 mL). The extracts were combined and washed with water (300 mL)and brine (300 mL). The organic solution was dried over sodium sulfate,filtered, and concentrated. The product was purified by silica gelchromatography (90:10:1 CH₂Cl₂/methanol/NOH) to yield 153 (900 mg, 39%).

Example 139 Preparation of 153.HCl

To a stirred solution of 153 (100 mg, 0.194 mmol) in ethyl acetate (10mL), was added 2 M HCl in diethyl ether (116 μL). After 20 min, thesolution was concentrated to afford the HCl salt of 153 in quantitativeyield: mp 278-288° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.34 (brs, 1H),7.36-7.53 (m, 4H), 6.77-7.01 (m, 3H), 5.30 (brs, 1H), 4.65-5.20 (m, 4H),3.80-3.95 (m, 1H), 3.76 (s, 1H), 3.69 (s, 1H), 3.05-3.22 (m, 1H),2.03-2.30 (m, 4H), 1.35-1.71 (m, 10H); API MS m/z=516 [C₂₉H₃₇N₇O₂+H]⁺.

Example 140 Preparation of Compound 154

To a 0° C. stirred solution of 153 (300 mg, 0.582 mmol) in methylenechloride (12 mL) was added pyridine (70 μL), acetic anhydride (54.0 μL,0.582 mmol), and DMAP (7.10 mg, 0.582 mmol). The solution was stirredfor 40 min before warming to room temperature. After 3 h, another 100 μLacetic anhydride was added. After stirring for 1 h, the reaction mixturewas concentrated and dried in vacuo. The material was purified by silicagel chromatography (90:10:1 CH₂Cl₂/methanol/NH₄OH) to yield 154: mp185-192° C.; ¹H NMR (300 MHz, CD₃OD) δ 7.78 (s, 1H), 7.29-7.45 (m, 4H),6.87-6.98 (m, 1H), 6.75-6.86 (m, 2H), 4.75 (s, 2H), 4.55-4.68 (m, 1H),3.74 (s, 3H), 3.67 (s, 3H), 1.97-2.13 (m, 2H), 1.81-1.96 (m, 5H), 1.53(d, 6H), 1.21-1.40 (m, 4H); API MS m/z=558 [C₃₁ H₃₉N₇O₃+H]⁺.

Example 141 Preparation of Compound 155

To a solution of 153 (242 mg, 0.469 mmol) in 1,2-dichloroethane (1.5 mL)was added propionaldehyde (27.0 μL, 0.375 mmol). After stirring for 15min under nitrogen, sodium triacetoxyborohydride (140 mg, 0.657 mmol)was added. The reaction mixture was stirred under nitrogen overnightbefore being concentrated. Purification by silica gel chromatography(90:10:1 CH₂Cl₂/methanol/NH₄OH) yielded 155.

Example 142 Preparation of Compound 155.HCl

To a stirred solution of 155 (30.0 mg, 0.054 mmol) in ethyl acetate (6mL) was added 2 M HCl in diethyl ether (40.0 μL). After 20 min, thesolution was concentrated and dried in vacuo to afford the HCl salt of155 in quantitative yield: mp 264-268° C.; ¹H NMR (300 MHz, CD₃OD) δ8.41 (brs, 1H), 7.46 (m, 4H), 6.98 (d, 1H), 6.76-6.93 (m, 2H), 4.63-5.07(m, 4H), 3.89 (m, 1H), 3.77 (s, 3H), 3.71 (s, 3H), 3.13 (m, 1H), 2.97(m, 2H), 2.10-2.35 (m, 4H), 1.35-1.88 (m, 12H), 1.02 (t, 3H); API MSm/z=558 [C₃₂H₄₃N₇O₂+H]⁺.

Example 143 Preparation of Compound 156

To a solution of 153 (242 mg, 0.469 mmol) in 1,2-dichloroethane (1.5 mL)was added propionaldehyde (27.0 μL, 0.375 mmol). After stirring for 15min under nitrogen, sodium triacetoxyborohydride (140 mg, 0.657 mmol)was added. The reaction mixture stirred under nitrogen overnight beforebeing concentrated. Purification by silica gel chromatography (90:10:1CHCl₃/methanol/NH₄OH) yielded 156.

Example 144 Preparation of Compound 156.HCl

To a stirred solution of 156 (160 mg, 0.267 mmol) in ethyl acetate (8mL) was added 2 M HCl in diethyl ether (170 μL). After 20 min, thesolution was concentrated and dried in vacuo to afford the HCl salt of156 in quantitative yield: mp 235-243° C.; ¹H NMR (300 MHz, CD₃OD) δ8.43 (brs, 1H), 7.47 (m, 4H), 6.94-7.04 (d, 1H), 6.80-6.93 (m, 2H),4.67-5.10 (m, 4H), 3.81-3.98 (m, 1H), 3.76 (s, 3H), 3.71 (s, 3H),2.93-3.48 (m, 5H), 2.00-2.35 (m, 4H), 1.36-1.90 (m, 14H), 1.01 (t, 6H);API MS m/z=601 [C₃₅H₄₉N₇O₂+H]⁺.

Example 145 Preparation of Compound 157

To a solution of 61 (1.50 g, 3.27 mmol) in ethylene glycol dimethylether (75 mL), was added 5-methyl-2-thiopheneboronic acid (1.40 g, 9.82mmol), tris(dibenzylideneacetone)dipalladium(0) (100 mg, 0.109 mmol),triphenylphosphine (430 mg, 1.64 mmol), and 2 M sodium carbonatesolution (10 mL). The solution was refluxed under nitrogen for 2 d.After cooling to room temperature, the reaction mixture was diluted with100 mL water. The aqueous solution was extracted with methylene chloride(3×100 mL). The extracts were combined and washed with water (300 mL)and brine (300 mL). The organic solution was dried over sodium sulfate,filtered, and concentrated. The product was purified by silica gelchromatography (90:10:1 CHCl₃/methanol/NH₄OH) to yield 157 (1.04 g,67%).

Example 146 Preparation of Compound 157.HCl

To a stirred solution of 157 (150 mg, 0.269 mmol) in ethyl acetate (10mL) was added 2 M HCl in diethyl ether (161 μL). After 20 min, thesolution was concentrated to afford the HCl salt of 157 in quantitativeyield: mp 300° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.35 (brs, 1H), 7.55 (d,2H), 7.39 (d 2H), 7.17 (d, 1H), 6.74 (d, 1H), 4.62-5.40 (m, 5H),3.78-3.94 (m, 1H), 3.03-3.20 (m, 1H), 2.47 (s, 3H), 1.98-2.29 (m, 4H),1.44-1.74 (m, 10H); API MS m/z=476 [C₂₆H₃₃N₇S+H]⁺.

Example 147 Preparation of Compound 159

To a solution of 157 (300 mg, 0.631 mmol) in 1,2-dichloroethane (2.0 mL)was added propionaldehyde (36.0 μL, 0.505 mmol). After stirring for 30min under nitrogen, sodium triacetoxyborohydride (190 mg, 0.883 mmol)was added. The reaction mixture stirred under nitrogen for 3 h beforebeing concentrated. Purification by silica gel chromatography (90:10:1CHCl₃/methanol/NH₄OH) yielded 159: mp 150-155° C.; ¹H NMR (300 MHz,CD₃OD) δ 7.81 (s, 1H), 7.51 (d, 2H), 7.33 (d, 2H), 7.11 (d, 1H), 6.73(d, 1H), 4.80-5.05 (m, 1H), 4.55-4.78 (m, 3H), 3.65-3.80 (m, 1H), 3.01(m, 1H), 2.91 (t, 2H), 2.47 (s, 3H), 2.02-2.19 (m, 4H), 1.60-1.75 (m,8H), 1.54 (d, 6H), 1.19-1.50 (m, 4H), 1.01 (t, 3H); API MS m/z=518[C₂₉H₃₉N₇S+H]⁺.

Example 148 Preparation of Compound 158

To a 0° C. stirred solution of 157 (300 mg, 0.631 mmol) in methylenechloride (12 mL) was added pyridine (76 μL), acetic anhydride (58 μL,0.631 mmol), and DMAP (7.7 mg, 0.063 mmol). After 20 min, the reactionmixture warmed to room temperature. After mixing overnight, the reactionmixture was concentrated and dried in vacuo. The material was purifiedby silica gel chromatography (90:10:1 CHCl₃/methanol/NH₄OH) to yield158: mp 225-230° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.39-7.51 (m, 3H), 7.32(d, 2H), 7.07 (d, 1H), 6.71 (m, 1H), 6.14 (brs, 1H), 5.32 (d, 1H),4.53-4.82 (m, 4H), 3.74 (m, 2H), 2.50 (s, 3H), 1.90-2.23 (m, 7H), 1.51(d, 6H), 1.12-1.38 (m, 4H); API MS m/z=518 [C₂₈H₃₅N₇OS+H]⁺.

Example 149 Preparation of Compound 160

To a suspension of 61 (1.00 g, 2.18 mmol) in ethylene glycol dimethylether (50 mL), was added 4-methylthiophene-2-boronic acid (0.93 g, 6.54mmol), tris(dibenzylideneacetone)dipalladium(0) (67.0 mg, 0.073 mmol),triphenylphosphine (287 mg, 1.09 mmol), and 2 M sodium carbonatesolution (10 mL). The solution was refluxed under nitrogen for 2 d.After cooling to room temperature, the reaction mixture was diluted with100 mL water. The aqueous solution was extracted with methylene chloride(3×100 mL). The extracts were combined and washed with water (300 mL)and brine (300 mL). The organic solution was dried over sodium sulfate,filtered, and concentrated. The product was purified by silica gelchromatography (90:10:1 CHCl₃/methanol/NH₄OH) to yield 160 (450 mg,44%).

Example 150 Preparation of Compound 160.HCl

To a stirred solution of 160 (50.0 mg, 0.105 mmol) in ethyl acetate (4mL) was added 2 M HCl in diethyl ether (100 μL). After 20 min, thesolution was concentrated to afford the HCl salt of 160 in quantitativeyield: mp 308-315° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.31 (brs, 1H), 7.60(d, 2H), 7.39 (d, 2H), 7.20 (s, 1H), 6.94 (s, 1H), 4.65-5.10 (m, 3H),3.86 (m, 1H), 3.13 (m, 1H), 2.26 (s, 3H), 2.00-2.12 (m, 4H), 1.32-1.72(m, 10H); API MS m/z=476 [C₂₆H₃₃N₇S+H]⁺.

Example 151 Preparation of Compounds 162 and 163

To a stirred solution of 160 (300 mg, 0.631 mmol) in 1,2-dichloromethane(3 mL) was added propionaldehyde (36.0 μL). After stirring undernitrogen for 15 min, sodium triacetoxyborohydride (161 mg, 0.757 mmol)was added. The mixture was stirred overnight. The reaction wasconcentrated and purified by silica gel chromatography (95:4.5:1CHCl₃/methanol/NH₄OH) to yield 162 (80 mg, 31%), and 163(110 mg). For162: ¹H NMR (300 MHz, CD₃OD) δ7.79 (s, 1H), 7.54 (d, 2H), 7.33 (d, 2H),7.16 (s, 1H), 6.89 (s, 1H), 4.71 (s, 2H), 4.60 (m, 1H), 3.70 (m, 1H),3.31 (t, 2H), 2.42-2.62 (m, 3H), 2.23 (s, 3H), 1.87-2.10 (m, 4H), 1.51(d, 6H), 1.10-1.33 (m, 4H), 0.94 (t, 3H).

Example 152 Preparation of Compound 162.HCl

To a stirred solution of 162 (80.0 mg, 0.155 mmol) in ethyl acetate (6mL) was added 2 M HCl in diethyl ether (100 μL). After 20 min, thesolution was concentrated to afford the HCl salt of 162 in quantitativeyield: mp 225-240° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.36 (brs, 1H), 7.62(d, 2H), 7.42 (d, 2H), 7.22 (s, 1H), 6.95 (s, 1H), 4.65-5.05 (m, 4H),3.87 (m, 1H), 3.11 (m, 1H), 2.98 (t, 2H), 2.07-2.36 (m, 5H), 1.32-1.85(m, 14H), 1.04 (t, 3H); API MS m/z=518 [C₂₉H₃₉N₇S+H]⁺.

Example 153 Preparation of Compound 163.HCl

To a stirred solution of 163 (110 mg, 0.196 mmol) in ethyl acetate (8mL) was added 2 M HCl in diethyl ether (120 μL). After 20 min, thesolution was concentrated to afford the HCl salt of 163 in quantitativeyield: mp 227-229° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.39 (brs, 1H), 7.60(d, 2H), 7.41 (d, 2H), 7.22 (s, 1H), 6.94 (s,1H), 4.63-5.10 (m, 3H),3.85 (m, 1H), 2.93-3.47 (m, 5H), 1.92-2.40 (m, 7H), 1.32-1.90 (m, 14H),1.04 (t, 6H); API MS m/z=560 [C₃₂H₄₅N₇S+H]⁺.

Example 154 Preparation of Compound 161

To a 0° C. stirred solution of 160 (100 mg, 0.210 mmol) in methylenechloride (5 mL) were added pyridine (26.0 μL), acetic anhydride (20.0μL, 0.210 mmol), and DMAP (3.0 mg, 0.021 mmol). After 40 min, thereaction mixture warmed to room temperature. The reaction mixture wasconcentrated and dried in vacuo. The material was purified by silica gelchromatography (90:10:1 CHCl₃/methanol/NH₄OH) to yield 161: mp 222-223°C.; ¹H NMR (300 MHz, CD₃OD) δ 7.78 (s, 1H), 7.52 (d, 2H), 7.35 (d, 2H),7.16 (s, 1H), 6.89 (s, 1H), 4.83-5.05 (m, 1H), 4.72 (s, 2H), 4.64 (m,1H), 3.73 (m, 1H), 3.61 (m, 1H), 2.25 (s, 3H), 1.97-2.13 (m, 2H),1.81-1.96 (m, 5H), 1.54 (d, 6H), 1.19-1.40 (m, 4H); API MS m/z=518[C₂₈H₃₅N₇OS+H]⁺.

Example 155 Preparation of Compound 164

To a solution of 61 (1.20 g, 2.62 mmol) in ethylene glycol dimethylether (75 mL), was added furan-3-boronic acid (0.88 g, 7.85 mmol),tris(dibenzylideneacetone)dipalladium(0) (80.0 mg, 0.087 mmol),triphenylphosphine (343 mg, 1.31 mmol), and 2 M sodium carbonatesolution (10 mL). The solution was refluxed under nitrogen overnight.After cooling to room temperature, the reaction mixture was diluted with100 mL water. The aqueous solution was extracted with methylene chloride(3×150 mL). The extracts were combined and washed with water (450 mL)and brine (450 mL). The organic solution was dried over sodium sulfate,filtered, and concentrated. The product was purified by silica gelchromatography (90:10:1 CHCl₃/methanol/NH₄OH) to yield 164 (700 mg,60%).

Example 156 Preparation of Compound 164.HCl

To a stirred solution of 164 (100 mg, 0.224 mmol) in ethyl acetate (6mL) was added 2 M HCl in diethyl ether (135 μL). After 20 min, thesolution was concentrated to afford the HCl salt of 164 in quantitativeyield: mp 320-330° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.35 (brs, 1H), 7.90(s, 1H), 7.57 (m, 3H), 7.42 (d, 2H), 6.79 (s, 1H), 4.65-5.07 (m, 5H),3.87 (m, 1H), 3.13 (m, 1H), 2.00-2.30 (m, 4H), 1.35-1.75 (m, 10H); APIMS m/z=446 [C₂₅H₃₁N₇O+H]⁺.

Example 157 Preparation of Compound 166

To a stirred solution of 164 (200 mg, 0.449 mmol) in 1,2-dichloromethane(2 mL) was added propionaldehyde (26.0 μL). After stirring undernitrogen for 20 min, sodium triacetoxyborohydride (114 mg, 0.539 mmol)was added. The mixture was stirred overnight. The reaction wasconcentrated and purified by silica gel chromatography (90:10:1CHCl₃/methanol/NH₄OH) to yield 166.

Example 158 Preparation of Compound 166.HCl

To a stirred solution of 166 (120 mg, 0.227 mmol) in ethyl acetate (7mL) was added 2 M HCl in diethyl ether (150 μL). After 20 min, thesolution was concentrated to afford the HCl salt of 166 in quantitativeyield: mp 285-286° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.42 (brs, 1H), 7.90(s, 1H), 7.49-7.62 (m, 3H), 7.43 (d, 2H), 6.80 (s, 1H), 4.76-5.10 (m,3H), 3.91 (m, 1H), 2.93-3.49 (m, 5H), 2.00-2.40 (m, 4H), 1.35-1.95 (m,14H), 1.03 (t, 6H); API MS m/z=530 [C₃₁H₄₃N₇O+H]⁺.

Example 159 Preparation of Compound 165

To a 0° C. stirred solution of 164 (200 mg, 0.449 mmol) in methylenechloride (8 mL) was added pyridine (55.0 μL), acetic anhydride (46.0 μL,0.449 mmol), and DMAP (6.0 mg, 0.045 mmol). After 40 min, the reactionmixture warmed to room temperature. After stirring overnight, thereaction mixture was concentrated and dried in vacuo. The material waspurified by silica gel chromatography (90:10:1 CHCl₃/methanol/NH₄OH) toyield 165 (190 mg, 87%): mp 241-243° C.; ¹H NMR (300 MHz, CD₃OD) δ 7.86(s, 1H), 7.80 (s, 1H), 7.45-7.54 (m, 3H), 7.32-7.40 (m, 2H), 6.76 (s,1H), 4.71 (s, 2H), 4.62 (m, 1H), 3.74 (m, 1H), 3.61 (m, 1H), 1.73-2.11(m, 7H), 1.54 (d, 6H), 1.20-1.40 (m, 4H); API MS m/z=488[C₂₇H₃₃N₇O₂+H]⁺.

Example 160 Preparation of Compounds 167 and 168

Compound 75 (0.500 g, 1.10 mmol) was dissolved in 1,2-dichloroethane (10mL). To this stirred solution was added acetaldehyde (0.054 g, 1.22mmol) and sodium triacetoxyborohydride (0.360 g, 1.71 mmol). After 1.5h, the reaction was quenched with saturated sodium bicarbonate solution(10 mL). The mixture was extracted with ethyl acetate (10 mL). Theorganic layers were combined, dried over sodium sulfate, andconcentrated. The resulting material was purified via silica gelchromatography (60:1:1 CH₂Cl₂/methanol/triethylamine) to yield 167 (213mg, 40%), and 168 (109 mg, 19%).

Example 161 Preparation of Compound 167.HCl

To a stirred solution of 167 (213 mg, 0.440 mmol) in ethyl acetate (10mL) was added 2 M HCl in diethyl ether (0.264 mL). The organic liquidwas concentrated to afford the HCl salt of 167 in quantitative yield: ¹HNMR (300 MHz, CD₃OD) δ 8.30 (brs, 1H), 7.30-7.63 (m, 10H), 4.71-4.80 (m,3H), 3.65-3.72 (m, 1H), 3.48 (q, 2H), 3.10 (brs, 2H), 2.10-2.20 (m, 4H),1.60 (d, 6H), 1.30-1.59 (m, 7H); API MS m/z=484 [C₂₉H₃₇N₇+H]⁺.

Example 162 Preparation of Compound 168.HCl

To a stirred solution of 168 (109 mg, 0.213 mmol) in ethyl acetate (10mL) was added 2 M HCl in diethyl ether (0.128 mL). The organic liquidwas concentrated to afford the HCl salt of 168 in quantitative yield: ¹HNMR (300 MHz, CD₃OD) δ 7.25-7.67 (m, 10H), 4.60-4.80 (m, 3H), 3.68-3.80(m, 1H), 3.48 (q, 4H), 2.78-2.95 (m, 4H), 2.02-2.17 (m, 2H), 1.10-1.59(m, 10H), 1.35 (t, 6H); API MS m/z=512 [C₃₁H₄₁N₇+H]⁺.

Example 163 Preparation of Compounds 169 and 170

Compound 75 (0.500 g, 1.10 mmol) was dissolved in 1,2-dichloroethane (10mL). To this stirred solution was added butyraldehyde (0.072 g, 1.00mmol) and sodium triacetoxyborohydride (0.297 g, 1.40 mmol). After 2.5h, the reaction was quenched with saturated sodium bicarbonate solution(10 mL). The mixture was extracted with ethyl acetate (10 mL). Theorganic layers were combined, dried over sodium sulfate, andconcentrated. The resulting material was purified via silica gelchromatography (200:10:1 CH₂Cl₂/methanol/NH₄OH) to yield 169 (180 mg,32%), and 170 (160 mg, 26%).

Example 164 Preparation of Compound 169.HCl

To a stirred solution of 169 (170 mg, 0.332 mmol) in ethyl acetate (10mL) was added 2 M HCl in diethyl ether (0.199 mL). The organic liquidwas concentrated to afford the HCl salt of 169 in quantitative yield: ¹HNMR (300 MHz, CD₃OD) δ 8.30-8.34 (m, 1H), 7.30-7.68 (m, 10H), 5.30 (brs,1H), 4.654.90 (m, 4H), 3.80-3.92 (m, 2H), 2.94-3.35 (m, 4H), 2.15-2.32(m, 4H), 1.41-1.75 (m, 12H), 1.00 (t, 3H).

Example 165 Preparation of Compound 171

To a stirred, 0° C. solution of 169 (125 mg, 0.228 mmol) in methylenechloride (10 mL), was added pyridine (46 μL), DMAP (6.0 mg, 0.046 mmol),and acetic anhydride (24.0 μL, 0.251 mmol). After 1 h under a nitrogenatmosphere, the reaction mixture was warmed to room temperature. Afterstirring overnight, another 2.2 equivalents of acetic anhydride and 0.2equivalents of DMAP were added and the mixture was heated to reflux.Following concentration, the material was diluted with ethyl acetate (20mL) and saturated sodium bicarbonate solution (20 mL). The organic layerwas concentrated and dried in vacuo. The resulting material was purifiedvia silica gel chromatography (90:10:1 CH₂Cl₂/methanol/NH₄OH) andtrituration with hexanes to yield 171 (26 mg): API MS m/z=554[C₃₃H₄₃N₇O+H]⁺.

Example 166 Preparation of Compound 170.HCl

To a stirred solution of 170 (150 mg, 0.264 mmol) in ethyl acetate (10mL) was added 2 M HCl in diethyl ether (0.158 mL). The organic liquidwas concentrated to afford the HCl salt of 170 in quantitative yield: ¹HNMR (300 MHz, CD₃OD) δ 8.15-8.25 (m, 1H), 7.31-7.68 (m, 10H), 4.65-4.90(m, 3H), 3.70-3.95 (m, 1H), 2.95-3.41 (m, 6H), 2.05-2.32 (m, 4H),1.31-1.79 (m, 18H), 1.00 (t, 6H).

Example 167 Preparation of Compounds 172 and 173

Compound 75 (0.500 g, 1.10 mmol) was dissolved in 1,2-dichloroethane (10mL). To this stirred solution was added cyclopropanecarboxaldehyde(0.070 g, 1.00 mmol) and sodium triacetoxyborohydride (0.297 g, 1.40mmol). After 3 h, the reaction was quenched with saturated sodiumbicarbonate solution (10 mL). The mixture was extracted with ethylacetate (10 mL). The organic layers were combined, dried over sodiumsulfate, and concentrated. The resulting material was purified viasilica gel chromatography (200:10:1 CH₂Cl₂/methanol/NH₄OH) to yield 172(103 mg, 18%), and 173 (160 mg, 26%).

Example 168 Preparation of Compound 172.HCl

To a stirred solution of 172 (103 mg, 0.202 mmol) in ethyl acetate (10mL) was added 2 M HCl in diethyl ether (0.121 mL). The organic liquidwas concentrated to afford the HCl salt of 172 in quantitative yield: ¹HNMR (300 MHz, CD₃OD) δ 8.30 (brs, 1H), 7.30-7.69 (m, 10H), 4.69-4.92 (m,4H), 3.80-3.92 (m, 1H), 2.84-3.19 (m, 3H), 2.11-2.28 (m, 4H), 1.37-1.72(m, 10H), 1.05-1.15 (m, 1H), 0.68-0.74 (m, 2H), 0.38-0.42 (m, 2H).

Example 169 Preparation of Compound 173.HCl

To a stirred solution of 173 (160 mg, 0.284 mmol) in ethyl acetate (10mL) was added 2 M HCl in diethyl ether (0.170 mL). The organic liquidwas concentrated to afford the HCl salt of 173 in quantitative yield: ¹HNMR (300 MHz, CD₃OD) δ 8.30-8.41 (m, 1H), 7.30-7.68 (m, 10H), 5.30 (brs,1H), 4.68-4.90 (m, 4H), 3.55-3.95 (m, 2H), 3.05-3.20 (m, 4H), 2.00-2.32(m, 4H), 1.10-1.90 (m, 10H), 0.75-0.80 (m, 4H), 0.35-0.50 (m, 4H).

Example 170 Preparation of Compounds 174 and 175

Compound 75 (1.50 g, 3.29 mmol) was dissolved in 1,2-dichloroethane (30mL). To this stirred solution was added propionaldehyde (0.174 g, 2.99mmol) and sodium triacetoxyborohydride (0.888 g, 4.19 mmol). After 1.5h, the reaction was quenched with saturated sodium bicarbonate solution(30 mL). The mixture was extracted with ethyl acetate (30 mL). Theorganic layers were combined, dried over sodium sulfate, andconcentrated. The resulting material was purified via silica gelchromatography (200:10:1 CH₂Cl₂/methanol/NH₄OH) to yield 174 (317 mg,19%): ¹H NMR (300 MHz, CD₃OD) δ 7.26-7.80 (m, 10H), 4.62-4.81 (m, 3H),3.74 (brs, 1H), 2.41-2.62 (m, 3H), 1.90-2.11 (m, 4H), 1.52 (d, 6H),1.12-1.52 (m, 8H), 0.92 (t, 3H), and 175 (320 mg, 18%): ¹H NMR (300 MHz,CD₃OD) δ 8.18-8.28 (m, 1H), 7.28-7.68 (m, 10H), 4.65-4.90 (m, 3H),3.81-3.94 (m, 1H), 2.94-3.25 (m, 4H), 2.02-2.31 (m, 6H), 1.40-1.81 (m,14H), 1.05 (t, 6H).

Example 171 Preparation of Compound 267

The HCl salt of 167 (10 mg, 0.037 mmol), was dispersed in ethyl acetateand neutralized with sodium bicarbonate. The organic material was driedover magnesium sulfate and concentrated. The solid was dissolved in dryCH₂Cl₂ (10 mL) and cooled to 0° C. To the solution was added DMAP (9mg), pyridine (0.074 mL) and acetic anhydride (0.037 mL). The ice bathwas removed after 1 h. After being stirred overnight, additional DMAPand Ac₂O was added in portions to consume starting material by TLCanalysis. The mixture was heated to reflux for 2 d. Upon cooling, themixture was concentrated in vacuo, then neutralized with aqueous sodiumbicarbonate, extracted with ethyl acetate, dried and concentrated. Theresidue was purified by chromatography to provide 267: API MS m/z=526[C₃₁H₃₉N₇O+H]⁺.

Example 172 Preparation of Compound 177

To a solution of 61 (1.00 g, 2.21 mmol) and 3-tolylboronic acid (0.33 g,2.43 mmol) in tetrahydrofuran (5 mL) was addedtris(dibenzylideneacetone)dipalladium(0) (0.010 g, 0.011 mmol),tri-tert-butylphosphine (5.5 mg, 0.027 mmol), and potassium fluoride(0.42 g, 7.29 mmol). After mixing overnight at room temperature, thereaction mixture was refluxed for 24 h and cooled to room temperature.The reaction mixture was diluted with ether (50 mL) and filtered throughCelite. The organic liquid was concentrated and the resulting materialwas purified via silica gel chromatography (90:10:1CH₂Cl₂/methanol/NH₄OH) to yield 177 (0.70 g, 71%).

Example 173 Preparation of Compound 177.HCl

To a stirred solution of 177 (449 mg, 0.956 mmol) in ethyl acetate (10mL) was added 2 M HCl in diethyl ether (575 μL). The organic liquid wasconcentrated to afford the HCl salt of 177 in quantitative yield: mp186-195° C.; ¹H NMR (300 MHz, CD₃OD) δ 7.82 (s, 1H), 7.54 (d, 2H),7.20-7.48 (m, 5H), 7.12 (d, 1H), 4.83-5.10 (m, 2H), 4.77 (s, 2H), 4.64(m, 1H), 3.77 (m, 1H), 3.03 (m, 1H), 2.38 (s, 3H), 1.93-2.20 (m, 4H),1.19-1.70 (m, 10H); API MS m/z=470 [C₂₈H₃₅N₇+H]⁺.

Example 174 Preparation of Compound 178

To a stirred solution of 177 (219 mg, 0.466 mmol) in methylene chloride(25 mL) was added acetic anhydride (48 μL, 0.513 mmol), DMAP (5.7 mg,0.047 mmol), and pyridine (57.0 μL, 0.699 mmol). The mixture was placedunder a nitrogen atmosphere and immersed in an ice water bath. After 30min, the reaction mixture was warmed to room temperature and stirred foranother 1.5 h. The solution was concentrated and the resulting materialwas purified via silica gel chromatography (95:5:1CH₂Cl₂/methanol/NH₄OH) to afford 178.

Example 175 Preparation of Compound 178.HCl

To a stirred solution of 178 (50.0 mg, 0.098 mmol) in ethyl acetate (5mL) was added 2 M HCl in diethyl ether (59.0 μL). The organic liquid wasconcentrated to afford the HCl salt of 178 in quantitative yield: mp165-174° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.26 (brs, 1H), 7.61 (d, 2H),7.47 (d, 2H), 7.24-7.41 (m, 3H), 7.15 (d, 1H), 4.62-5.08 (m, 4H), 3.83(m, 1H), 3.67 (m, 1H), 2.39 (s, 3H), 1.87-2.20 (m, 7H), 1.60 (d, 6H),1.40 (m, 4H); API MS m/z=512 [C₃₀H₃₇N₇O+H]⁺.

Example 176 Preparation of Compound 179

To a solution of 61 (2.00 g, 4.36 mmol) and 3-methoxyphenyl boronic acid(0.73 g, 4.79 mmol) in tetrahydrofuran (10 mL) was addedtris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.022 mmol),tri-tert-butylphosphine (10.0 mg, 0.052 mmol), and potassium fluoride(0.84 g, 14.39 mmol). After refluxing overnight, the reaction mixturewas diluted with ether (50 mL) and filtered through Celite. The organicliquid was concentrated and the resulting material was purified viasilica gel chromatography (95:5:1 CH₂Cl₂/methanol/NH₄OH) to yield 179(1.18 g, 56%).

Example 177 Preparation of Compound 179.HCl

To a stirred solution of 179 (980 mg, 2.02 mmol) in ethyl acetate (10mL) was added 2 M HCl in diethyl ether (1.21 mL). The organic liquid wasconcentrated to afford the HCl salt of 179 in quantitative yield: mp182-189° C.; ¹H NMR (300 MHz, CD₃OD) δ 7.80 (s, 1H), 7.54 (d, 2H), 7.40(d, 2H), 7.30 (t, 1H), 7.12 (m, 2H), 6.87 (m, 1H), 4.76 (s, 2H), 4.62(m, 1H), 3.67-3.90 (m, 4H), 2.94 (m, 1H), 1.90-2.20 (m, 4H), 1.17-1.65(m, 10H); API MS m/z=486 [C₂₈H₃₅N₇O+H]⁺.

Example 178 Preparation of Compound 180

To a stirred solution of 179 (200 mg, 0.412 mmol) in methylene chloride(25 mL) was added acetic anhydride (43 μL, 0.450 mmol), DMAP (5.0 mg,0.041 mmol), and pyridine (50.0 μL, 0.618 mmol). The mixture was placedunder a nitrogen atmosphere and immersed in an ice water bath. After 30min, the reaction mixture was warmed to room temperature and stirred foranother 1.5 h. The solution was concentrated and the resulting materialwas purified via silica gel chromatography (95:5:1CH₂Cl₂/methanol/NH₄OH) to afford 180.

Example 179 Preparation of Compound 180.HCl

To a stirred solution of 180 (60.0 mg, 0.114 mmol) in ethyl acetate (5mL) was added 2 M HCl in diethyl ether (68.0 μL). The organic liquid wasconcentrated to afford the HCl salt of 180 in quantitative yield: ¹H NMR(300 MHz, CD₃OD) δ 8.20 (brs, 1H), 7.62 (d, 2H), 7.46 (d, 2H), 7.34 (t,1H), 7.10-7.20 (m, 2H), 6.90 (1H), 4.60-5.10 (m, 4H), 3.83 (s, 3H), 3.64(m, 1H), 3.20-3.42 (m, 1H), 1.87-2.18 (m, 7H), 1.60 (d, 6H), 1.22-1.50(m, 4H); API MS m/z=528 [C₃₀H₃₇N₇O₂+H]⁺.

Example 180 Preparation of Compound 181

To a solution of 61 (2.00 g, 4.36 mmol) and furan-2-boronic acid (1.50g, 13.1 mmol) in ethylene glycol dimethyl ether (150 mL) was addedtris(dibenzylideneacetone)dipalladium(0) (120 mg, 0.130 mmol),tri-tert-butylphosphine (570 mg, 2.18 mmol), and 2 M sodium carbonatesolution (12.5 mL, 25.3 mmol). After refluxing overnight, 2 moreequivalents of furan-2-boronic acid were added. The reaction wasrefluxed for 24 h, cooled to room temperature, and diluted with water(50 mL). The aqueous mixture was extracted with methylene chloride (3×80mL). The extracts were combined and washed with water (250 mL) and brine(250 mL). The organic phase was dried over sodium sulfate and filtered.The organic liquid was concentrated and the resulting material waspurified via silica gel chromatography (95:5:1 CH₂Cl₂/methanol/NH₄OH) toyield 181.

Example 181 Preparation of Compound 181.HCl

To a stirred solution of 181 (600 mg, 1.35 mmol) in ethyl acetate (10mL) was added 2 M HCl in diethyl ether (0.810 mL). The organic liquidwas concentrated to afford the HCl salt of 181 (406 mg, 68%): ¹H NMR(300 MHz, CD₃OD) δ 8.06 (s, 1H), 7.66 (d, 2H), 7.53 (s, 1H), 7.41 (d,2H), 6.74 (m, 1H), 6.49 (m, 1H), 4.60-5.00 (m, 5H), 3.82 (m, 1H), 3.10(m, 1H), 1.95-2.20 (m, 4H), 1.20-1.61 (m, 10H); API MS m/z=446[C₂₅H₃₁N₇O+H]⁺.

Example 182 Preparation of Compound 182

To a stirred solution of 181 (750 mg, 1.68 mmol) in methylene chloride(30 mL) was added acetic anhydride (0.18 mL, 1.85 mmol), DMAP (20.8 mg,0.17 mmol), and pyridine (0.20 mL, 2.52 mmol). The mixture was placedunder a nitrogen atmosphere and immersed in an ice water bath. After 30min, the reaction mixture was warmed to room temperature and stirred foranother 1.5 h. The solution was concentrated and the resulting materialwas purified via silica gel chromatography (95:5:1CH₂Cl₂/methanol/NH₄OH) to afford 182 (530 mg, 65%).

Example 183 Preparation of Compound 182.HCl

To a stirred solution of 182 (300 mg, 0.620 mmol) in ethyl acetate (10mL) was added 2 M HCl in diethyl ether (0.370 mL). The organic liquidwas concentrated to afford the HCl salt of 182 in quantitative yield: ¹HNMR (300 MHz, CD₃OD) δ 8.25 (brs, 1H), 7.56-7.73 (m, 2H), 7.54 (s, 1H),7.30-7.47 (m, 2H), 6.75 (m, 1H), 6.49 (m, 1H), 4.60-5.05 (m, 4H),3.73-3.90 (m, 1H), 3.55-3.73 (m, 1H), 1.82-2.23 (m, 7H), 1.15-1.70 (m,10H); API MS m/z=488 [C₂₇H₃₃N₇O₂+H]⁺.

Example 184 Preparation of Compound 183

To a stirred mixture of 6-chloronicotinamide (5.00 g, 31.9 mmol) inethanol (13 mL) and toluene (80 mL) was added 3-fluorobenzeneboronicacid (4.92 g, 35.1 mmol) and 2 M sodium carbonate solution (32 mL). Thesuspension was heated to 80° C. and degassed with argon for 1 h. Aftercooling to room temperature, tetrakis(triphenylphophine)palladium(0)(1.11 g, 0.958 mmol) was added. The reaction mixture was refluxed underargon for 3 h. After cooling to room temperature, the mixture wasdiluted with water (100 mL) and filtered. The filter cake was washedwith water and dried in vacuo to afford 183 (6.38 g, 92%).

Example 185 Preparation of Compound 184

To a stirred suspension of 183 (3.00 g, 13.9 mmol) in tetrahydrofuran(25 mL) was added dropwise 1 M borane in THF (97.0 mL, 97.0 mmol). Afterrefluxing for 2 h, the reaction mixture was cooled in an ice bath. Themixture was acidified to pH 1 with 2 N HCl and stirred for 1 h. The pHwas raised to a value of 10 by adding 6 N NaOH and the resultingsolution was extracted with ethyl acetate (3×50 mL). The extractionswere combined, washed with brine (150 mL), and dried over sodiumsulfate. The suspension was filtered and concentrated. The resultingmaterial was purified by precipitation as the HCl salt from an ethanolsolution. The product was recovered by filtration and dried in vacuo toyield 184 (1.69 g, 51%): ¹H NMR (300 MHz, CD₃OD) δ 8.92 (s, 1H), 8.41(d, 1H), 8.27 (d, 1H), 7.77-7.90 (m, 2H), 7.35-7.70 (m, 2H), 4.36 (s,2H).

Example 186 Preparation of Compound 185

The amine 184 (1.84 g, 7.69 mmol), 2,6-dichloropurine (1.31 g, 6.99mmol), and N,N-diisopropylethylamine (2.68 mL, 15.4 mmol) were dissolvedin ethanol (65 mL). After refluxing overnight, the solution was immersedin an ice water bath for 20 min. The mixture was filtered and cake waswashed with water. The cake was triturated with ethanol and diethylether and dried in vacuo to afford 185 (1.12 g, 47%).

Example 187 Preparation of Compound 186

To a stirred solution of 185 (1.00 g, 2.94 mmol) in dimethylsulfoxide(100 mL) was added potassium carbonate (2.19 g, 15.9 mmol) and2-iodopropane (0.88 mL, 8.81 mmol). The mixture was placed under anargon atmosphere and stirred overnight. The reaction mixture was pouredinto stirred water (300 mL) and the resulting solution was extractedwith ethyl acetate (3×300 mL). The extractions were combined, washedwith water (900 mL) and brine (900 mL), and dried over magnesiumsulfate. Following filtration, the organic liquid was concentrated. Thematerial was purified by recrystallization from ethyl acetate in hexanesto yield 186 (0.92 g, 82%).

Example 188 Preparation of Compound 187

In a sealed tube were combined 186 (640 mg, 1.67 mmol),trans-1,4-diaminocyclohexane (0.96 g, 8.36 mmol), and ethanol (3.5 mL).The reaction mixture was heated to 150° C. for 4 d and cooled to roomtemperature. The solution was poured into stirred ice water (5 mL) andthe resulting mixture was extracted with methylene chloride (3×5 mL).The extractions were combined, washed with water (15 mL) and brine (15mL), and dried over sodium sulfate. The organic liquid was concentrated.Purification by column chromatography (97:3 CH₂Cl₂/methanol) andtrituration with hexanes yielded the free base, 187: ¹H NMR (300 MHz,CDCl₃) δ 8.68 (s, 1H), 7.60-7.82 (m, 4H), 7.50 (s, 1H), 7.42 (q, 1H),7.11 (m, 1H), 6.07 (m, 1H), 4.85 (d, 2H), 4.60 (m, 2H), 3.74 (m, 1H),2.69 (m, 1H), 2.02-2.19 (m, 2H), 1.78-1.96 (m, 2H), 1.52 (d, 6H),1.10-1.36 (m, 4H); API MS m/z=475 [C₂₆H₃₁FN₈+H]⁺.

Example 189 Preparation of Compound 188

The free amine 187 (80.0 mg, 0.170 mmol) was dissolved in methylenechloride (4 mL). The solution was immersed in an ice water bath andacetic anhydride (17.5 μL, 0.185 mmol), DMAP (2.0 mg, 0.017 mmol), andpyridine (20.0 μL, 0.252 mmol) were added. After stirring for 30 min,the solution was warmed to room temperature and concentrated.Purification via silica gel chromatography and trituration with hexanesyielded 188 (67 mg, 78%): mp 199-230° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.71(s, 1H), 7.62-7.85 (m, 4H), 7.52 (s, 1H), 7.42 (m, 1H), 7.10 (m, 1H),6.01 (m, 1H), 5.28 (d, 1H), 4.81 (d, 2H), 4.62 (m, 2H), 3.72 (m, 2H),1.90-2.27 (m, 7H), 1.53 (d, 6H), 1.24 (m, 4H); API MS m/z=517[C₂₈H₃₃FN₈O+H]⁺.

Example 190 Preparation of Compound 189

To a stirred mixture of 6-chloronicotinamide (3.00 g, 19.2 mmol) inethanol (7.6 mL) and toluene (48 mL) were added 3-methoxyphenylboronicacid (3.20 g, 21.1 mmol) and 2 M sodium carbonate solution (19 mL). Thesuspension was heated to 80° C. and degassed with argon for 1 h. Aftercooling to room temperature, tetrakis(triphenylphophine)palladium(0)(664 mg, 0.575 mmol) was added. The reaction mixture was refluxed underargon for 3 h. After cooling to room temperature, the mixture wasdiluted with water (100 mL) and filtered. The filter cake was washedwith water and dried in vacuo to afford 189 (3.62 g, 83%).

Example 191 Preparation of Compound 190

To a stirred solution of 189 (3.00 g, 13.1 mmol) in tetrahydrofuran (25mL) was added dropwise 1 M borane in THF (92.0 mL, 92.0 mmol). Afterrefluxing for 4 h, the reaction mixture was cooled in an ice bath. Themixture was acidified to pH 1 with 2 N HCl and stirred for 1 h. The pHwas raised to a value of 10 by adding 6 N NaOH and the resultingsolution was extracted with ethyl acetate (3×50 mL). The extractionswere combined, washed with brine (150 mL), and dried over sodiumsulfate. The suspension was filtered and concentrated. The resultingmaterial was purified by precipitation as the HCl salt from an ethanolsolution. The product was recovered by filtration and dried in vacuo toyield 190 (1.81 g, 55%).

Example 192 Preparation of Compound 191

The amine 190 (1.80 g, 7.18 mmol), 2,6-dichloropurine (1.22 g, 6.53mmol), and N,N-diisopropylethylamine (1.86 g, 6.53 mmol) were dissolvedin ethanol (82 mL). After refluxing overnight, the dispersion wasimmersed in an ice water bath for 60 min. The mixture was filtered andcake was washed with water. The cake was triturated with ethanol anddiethyl ether and dried in vacuo to afford 191 (1.04 g, 44%).

Example 193 Preparation of Compound 192

To a stirred solution of 191 (1.04 g, 2.84 mmol) in dimethylsulfoxide(60 mL) was added potassium carbonate (2.12 g, 15.3 mmol) and2-iodopropane (0.85 mL, 8.52 mmol). The mixture was placed under anargon atmosphere and stirred overnight. The reaction mixture was pouredinto stirred water (60 mL) and the resulting solution was extracted withethyl acetate (3×60 mL). The extractions were combined, washed withwater (180 mL) and brine (180 mL), and dried over magnesium sulfate.Following filtration, the organic liquid was concentrated. The materialwas purified by recrystallization from ethyl acetate in hexanes (1:40)to yield 192.

Example 194 Preparation of Compound 193

In a sealed tube were combined 192 (400 mg, 1.09 mmol),trans-1,4-diaminocyclohexane (1.25 g, 10.9 mmol), and ethanol (4.0 mL).The reaction mixture was heated to 150° C. for 24 h and cooled to roomtemperature. The solution was filtered and the filtrate wasconcentrated. Purification by column chromatography (97:3CH₂Cl₂/methanol) yielded the free base, 193 (240 mg, 45%).

Example 195 Preparation of Compound 194

The free amine 193 (130 mg, 0.27 mmol) was dissolved in methylenechloride (6 mL). The solution was immersed in an ice water bath andacetic anhydride (28.0 μL, 0.294 mmol), DMAP (3.2 mg, 0.026 mmol), andpyridine (33.0 μL, 0.401 mmol) were added. After stirring for 30 min,the solution was warmed to room temperature and concentrated.Purification via prep-TLC (9:1 CH₂Cl₂/methanol) and trituration withethyl acetate yielded 194: mp 161-163° C.; ¹H NMR (300 MHz, CDCl₃) δ8.76 (s, 1H), 7.77 (d, 1H), 7.64 (d, 1H), 7.50 (m, 3H), 7.35 (t, 1H),6.73-7.00 (m, 2H), 5.33 (d, 1H), 4.50-4.92 (m, 4H), 3.56-4.00 (m, 5H),1.84-2.22 (m, 7H), 1.55 (d, 6H), 1.25 (m, 4H); API MS m/z=529[C₂₉H₃₆N₈O₂+H]⁺.

Example 196 Preparation of Compound 195

To a stirred mixture of 6-chloronicotinamide (2.00 g, 12.8 mmol) inethanol (5.0 mL) and toluene (32 mL) was added thiophene-2-boronic acid(1.80 g, 14.1 mmol) and 2 M sodium carbonate solution (13 mL). Thesuspension was heated to 80° C. and degassed with argon for 1 h. Aftercooling to room temperature, tetrakis(triphenylphophine)palladium(0)(443 mg, 0.383 mmol) was added. The reaction mixture was refluxed underargon for 3 h. After cooling to room temperature, another 0.950 gthiophene-2-boronic acid and 280 mgtetrakis(triphenylphophine)palladium(0) were added to the reactionmixture. It was refluxed for 4 h and cooled to room temperature. Themixture was diluted with water (50 mL) and filtered. The filter cake waswashed with water and dried in vacuo to afford 195 (1.65 g, 63%).

Example 197 Preparation of Compound 196

To a stirred solution of 195 (1.40 g, 6.86 mmol) in tetrahydrofuran (23mL) was added dropwise 1 M borane in THF (48.0 mL, 48.0 mmol). Afterrefluxing for 1 h, the reaction mixture was cooled in an ice bath. Themixture was acidified to pH 1 with 2 N HCl and stirred for 1 h. The pHwas raised to a value of 10 by adding 6 N NaOH and the resultingsolution was extracted with ethyl acetate (3×50 mL). The extractionswere combined, washed with brine (150 mL), and dried over sodiumsulfate. The suspension was filtered and concentrated. The resultingmaterial was purified by precipitation as the HCl salt from an ethanolsolution. The product was recovered by filtration and dried in vacuo toyield 196 (0.87 g, 56%).

Example 198 Preparation of Compound 197

The amine 196 (210 mg, 1.10 mmol), 2,6-dichloropurine (188 mg, 1.00mmol), and N,N-diisopropylethylamine (286 g, 2.21 mmol) were dissolvedin ethanol (12 mL). After refluxing overnight, the suspension wasimmersed in an ice water bath for 60 min. The mixture was filtered andcake was washed with water. The cake was triturated with ethanol anddiethyl ether and dried in vacuo to afford 197 (206 mg, 60%).

Example 199 Preparation of Compound 198

To a stirred solution of 197 (200 mg, 0.583 mmol) in dimethylsulfoxide(12 mL) was added potassium carbonate (435 mg, 3.15 mmol) and2-iodopropane (0.18 mL, 1.75 mmol). The mixture was placed under anargon atmosphere and stirred overnight. The reaction mixture was pouredinto stirred water (15 mL) and the resulting solution was extracted withethyl acetate (3×30 mL). The extractions were combined, washed withwater (90 mL) and brine (90 mL), and dried over magnesium sulfate.Following filtration, the organic liquid was concentrated to yield 198(200 mg, 89%).

Example 200 Preparation of Compound 199

In a sealed tube were combined 198 (100 mg, 0.260 mmol),trans-1,4-diaminocyclohexane (297 mg, 2.60 mmol), and ethanol (2.0 mL).The reaction mixture was heated to 150° C. for 2 d and cooled to roomtemperature. The solution was filtered and diluted with ethanol. Thefiltrate was concentrated, and converted to its HCl salt to afford 199:¹H NMR (300 MHz, CD₃OD) δ 9.00 (s, 1H), 8.72 (d, 2H), 8.46 (d, 1H), 8.27(m, 1H), 8.15 (d, 1H), 7.54 (m, 1H), 4.89-5.35 (3H), 4.04 (m, 1H), 3.35(m, 1H), 2.20-2.50 (m, 4H), 1.55-1.90 (m, 10H); ESI MS m/z=463[C₂₄H₃₀N₈S+H]⁺.

Example 201 Preparation of Compound 200

The free amine 199 (100 mg, 0.216 mmol) was dissolved in methylenechloride (5 mL). The solution was immersed in an ice water bath andacetic anhydride (20.0 μL, 0.216 mmol), DMAP (2.6 mg, 0.021 mmol), andpyridine (33.0 μL, 0.324 mmol) were added. After stirring for 30 min,the solution was warmed to room temperature and concentrated.Purification via prep-TLC (10:1 CH₂Cl₂/methanol) yielded 200 (20 mg): mp206-208° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.56 (s, 1H), 7.70 (d, 1H), 7.58(d, 1H), 7.53 (m, 2H), 7.37 (m, 1H), 7.10 (m, 1H), 6.15 (brs, 1H), 5.33(d, 1H), 4.76 (d, 2H), 4.61 (m, 2H), 3.70 (m, 2H), 1.75-2.15 (m, 7H),1.52 (d, 6H), 1.23 (m, 4H); API MS m/z=505 [C₂₆H₃₂N₈OS+H]⁺.

Example 202 Preparation of Compound 201

To a stirred solution of 6-chloronicotinamide (2.80 g, 17.9 mmol) inethanol (7.5 mL) and toluene (48 mL) was added furan-2-boronic acid(3.00 g, 26.8 mmol) and 2 M sodium carbonate solution (18 mL). Thesuspension was heated to 80° C. and degassed with argon for 1 h. Aftercooling to room temperature, tetrakis(triphenylphophine)palladium(0)(619 mg, 0.536 mmol) was added. The reaction mixture was refluxed underargon for 2 d then cooled to room temperature. The mixture was dilutedwith water (75 mL) and filtered. The filter cake was washed with waterand dried in vacuo to afford 201 (1.95 g, 58%).

Example 203 Preparation of Compound 202

To a stirred solution of 201 (1.69 g, 8.98 mmol) in tetrahydrofuran (34mL) was added dropwise 1 M borane in THF (50.0 mL, 50.0 mmol). Afterrefluxing for 2 h, the reaction mixture was cooled in an ice bath. Themixture was acidified to pH 1 with 2 N HCl and stirred for 1 h. The pHwas raised to a value of 10 by adding 6 N NaOH and the resultingsolution was extracted with ethyl acetate (3×50 mL). The extractionswere combined, washed with brine (150 mL), and dried over sodiumsulfate. The suspension was filtered and concentrated. The resultingmaterial was purified by precipitation as the HCl salt from an ethanolsolution. The product was recovered by filtration and dried in vacuo toyield 202 (1.12 g, 50%).

Example 204 Preparation of Compound 203

The amine 202 (177 mg, 1.02 mmol), 2,6-dichloropurine (173 mg, 0.920mmol), and N,N-diisopropylethylamine (267 g, 2.07 mmol) were dissolvedin ethanol (11 mL). After refluxing overnight, the suspension wasimmersed in an ice water bath for 60 min. The mixture was filtered andcake was washed with water. The cake was triturated with ethanol anddiethyl ether and dried in vacuo to afford 203 (166 mg, 54%).

Example 205 Preparation of Compound 204

To a stirred solution of 203 (166 mg, 0.508 mmol) in dimethylsulfoxide(11 mL) was added potassium carbonate (379 mg, 2.74 mmol) and2-iodopropane (0.150 mL, 1.52 mmol). The mixture was placed under anargon atmosphere and stirred overnight. The reaction mixture was pouredinto stirred water (15 mL) and the resulting solution was extracted withethyl acetate (3×30 mL). The extractions were combined, washed withwater (90 mL) and brine (90 mL), and dried over magnesium sulfate.Following filtration, the organic liquid was concentrated to yield 204(178 mg, 95%).

Example 206 Preparation of Compound 205

In a sealed tube were combined 204 (170 mg, 0.461 mmol),trans-1,4-diaminocyclohexane (526 mg, 4.61 mmol), and ethanol (2.5 mL).The reaction mixture was heated to 150° C. for 4 d and cooled to roomtemperature. The solution was filtered and concentrated to afford 205.

Example 207 Preparation of Compound 206

The free amine 205 (100 mg, 0.224 mmol) was dissolved in methylenechloride (5 mL). The solution was immersed in an ice water bath andacetic anhydride (21.0 μL, 0.224 mmol), DMAP (2.7 mg, 0.022 mmol), andpyridine (34.0 μL, 0.336 mmol) were added. After stirring for 30 min,the solution was stored at 0° C. overnight. Purification via prep-TLC(9:1 CH₂Cl₂/methanol) yielded 206 (43 mg): mp 216-218° C.; ¹H NMR (300MHz, CDCl₃) δ 8.63 (s, 1H), 7.72 (d, 1H), 7.61 (d, 1H), 7.50 (m, 2H),6.99 (m, 1H), 6.50 (m, 1H), 6.15 (brs, 1H), 5.36 (d, 1H), 4.79 (d, 2H),4.62 (m, 2H), 3.68 (m, 2H), 1.78-2.20 (m, 7H), 1.54 (d, 6H), 1.22 (m,4H); API MS m/z=489 [C₂₆H₃₂N₈O₂+H]⁺.

Example 208 Preparation of Compound 207

Prepared by reaction of 72 with ethylene diamine by general methodsdescribed above (91%): ¹H NMR (300 MHz, (CD₃)₂SO) δ 8.06 (brs, 3H), 7.65(d, 4H), 7.31-7.52 (m, 6H), 4.68-4.90 (m, 3H), 3.61 (m, 2H), 3.01 (m,2H), 1.54 (d, 6H); ESI MS m/z=402 [C₂₃H₂₇N₇+H]⁺.

Example 209 Preparation of Compound 208

Prepared by reaction of 207 under standard acetylation conditions (35%):¹H NMR (300 MHz, CDCl₃) δ 7.49-7.62 (m, 5H), 7.30-7.48 (m, 5H), 6.44(brs, 1H), 6.13 (brs, 1H), 5.05 (t, 1H), 4.82 (d, 2H), 4.65 (m, 1H),3.58 (m, 2H), 3.45 (m, 2H), 1.87 (s, 3H), 1.54 (d, 6H); ESI MS m/z=444[C₂₅H₂₉N₇O+H]⁺.

Example 210 Preparation of Compound 211

Prepared by reaction of 72 and 1,3-propanediamine (28%): ¹H NMR (300MHz, (CD₃)₂SO) δ 8.00-8.22 (m, 3H), 7.63-7.70 (d, 4H), 7.32-7.59 (m,6H), 4.84 (m, 2H), 4.70 (m, 1H), 4.43 (m, 2H), 2.88 (m, 2H), 1.88 (m,2H), 1.52 (d, 6H); ESI MS m/z=416 [C₂₄H₂₉N₇+H]⁺.

Example 211 Preparation of Compound 212

Prepared by reaction of 211 with acetic anhydride under standardconditions (44%): mp 106-107° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.50-7.62(m, 5H), 7.28-7.50 (m, 5H), 5.87 (brs, 2H), 4.93 (m, 1H), 4.84 (m, 2H),4.66 (m, 1H), 3.49 (m, 2H), 3.33 (m, 2H), 1.91 (s, 3H), 1.74 (m, 2H),1.55 (d, 6H); ESI MS m/z=458 [C₂₆H₃₁N₇O+H]⁺.

Example 212 Preparation of Compound 213

Prepared by the general methods described above (48%): ¹H NMR (300 MHz,CDCl₃) δ 7.29-7.66 (m, 10H), 6.40 (brs, 1H), 4.71-5.03 (m, 3H), 4.61 (m,1H), 3.30-3.55 (m, 2H), 2.73 (m, 2H), 2.32 (m, 2H), 1.38-1.85 (m, 10H);ESI MS m/z=430 [C₂₅H₃₁N₇+H]⁺.

Example 213 Preparation of Compound 214

Prepared by the general methods described above (45%): ¹H NMR (300 MHz,CDCl₃) δ 7.27-7.65 (m, 10H), 5.92 (m, 1H), 5.43 (m, 1H), 4.83 (m, 3H),4.66 (m, 1H), 3.46 (m, 2H), 3.25 (m, 2H), 1.93 (s, 3H), 1.76 (m, 3H),1.40-1.70 (m, 8H); ESI MS m/z=472 [C₂₇H₃₃N₇O+H]⁺.

Example 214 Preparation of Compounds 209 and 210

Prepared by the general methods described above. For 210 (17%): ¹H NMR(300 MHz, (CD₃)₂SO) δ 7.31-7.72 (m, 10H), 4.64-4.92 (m, 3H), 3.73 (m,4H), 2.84-3.33 (m, 6H), 1.43-1.79 (m, 10H), 0.85 (m, 6H); ESI MS m/z=486[C₂₉H₃₉N₇+H]⁺. For 209: ¹H NMR (300 MHz, CDCl₃) δ 7.26-7.63 (m, 10H),6.46 (brs, 1H), 5.83 (brs, 1H), 4.85 (m, 2H), 4.66 (m, 1H), 3.79 (d,2H), 3.11 (m, 2H), 2.76 (m, 2H), 1.76 (m, 2H), 1.50 (d, 6H), 0.84 (m,3H); ESI MS m/z=444 [C₂₆H₃₃N₇+H]⁺.

Example 215 Preparation of Compound 215

Prepared by the general methods described above: ¹H NMR (300 MHz, CDCl₃)δ 7.22-7.60 (m, 10H), 6.18 (brs, 1H), 5.11 (brs, 1H), 4.81 (m, 2H), 4.64(m, 1H), 3.40 (m, 2H), 2.87 (m, 2H), 2.77 (m, 2H), 1.70-2.00 (m, 4H),1.55-1.70 (m, 2H), 1.51 (m, 6H), 0.92 (t, 3H); ESI MS m/z=472[C₂₈H₃₇N₇+H]⁺.

Example 216 Preparation of Compound 216

Prepared by the general methods described above (71%): ¹H NMR (300 MHz,CDCl₃) δ 7.28-7.61 (m, 10H), 6.01 (brs, 1H), 4.86 (d, 2H), 4.66 (m, 1H),3.79-3.89 (m, 1H), 3.70-3.79 (m, 1H), 3.57-3.70 (m, 2H), 3.27-3.37 (m,1H), 2.10-2.23 (m, 1H), 1.68-1.82 (m, 1H), 1.55 (d, 6H); ESI MS m/z=428[C₂₅H₂₉N₇+H]⁺.

Example 217 Preparation of Compound 217

Prepared by the general methods described above: TLC silica gelR_(f)=0.52 (20:1:0.01-CH₂Cl₂/MeOH/NH₄OH).

Example 218 Preparation of Compound 218

Prepared by the general methods described above: ¹H NMR (300 MHz,(CD₃)₂SO) δ 8.02 (brs, 1H), 7.88 (s, 1H), 7.54-7.68 (m, 4H), 7.40-7.50(m, 3H), 7.30-7.40 (m, 1H), 7.26 (s, 1H), 6.77 (s, 1H), 4.50-4.72 (m,4H), 2.78 (t, 2H), 2.31 (m, 1H), 1.68 (d, 2H), 1.49 (d, 6H); ESI MSm/z=470 [C₂₇H₃₁N₇O+H]⁺.

Example 219 Preparation of Compound 219

Prepared by the general methods described above (66%): ¹H NMR (300 MHz,CDCl₃) δ 7.28-7.62 (m, 10H), 5.89 (brs, 1H), 4.86 (d, 4H), 4.67 (m, 1H),2.81 (t, 2H), 2.58 (d, 2H), 1.77 (d, 2H), 1.40-1.69 (m, 10H), 1.06-1.31(m, 2H); ESI MS m/z=456 [C₂₇H₃₃N₇+H]⁺.

Example 220 Preparation of Compound 221

The compound 220 (100 mg, 0.170 mmol) was dissolved in methanol (25 mL).To the stirred solution was added ammonium formate (100 mg), and Pd/C(10.0 mg). After refluxing for 2 h, more ammonium formate (100 mg) andPd/C (10.0 mg) were added. The reaction was cooled to room temperatureand filtered through Celite. The filtrate was concentrated in vacuo. Theresulting material was purified via silica gel chromatography (3:1:0.01CH₂Cl₂/MeOH/NH₄OH) to yield 221 (26.9 mg, 34%): ¹H NMR (300 MHz, CDCl₃)δ 7.29-7.63 (m, 10H), 5.95 (brs, 1H), 4.73-4.93 (m, 3H), 4.64 (m, 1H),3.32 (t, 2H), 3.10 (d, 2H), 2.59 (t, 2H), 1.76 (m, 2H), 1.54 (d, 6H),1.28 (m, 3H), 0.90 (m, 1H); ESI MS m/z=456 [C₂₇H₃₃N₇+H]⁺.

Example 221 Preparation of Compound 222

Prepared by the general methods described above: ¹H NMR (300 MHz, CDCl₃)δ 7.28-7.61 (m, 10H), 6.20 (brs, 1H), 4.70-4.91 (m, 3H), 4.54-4.70 (m,1H), 4.28 (brs, 1H), 3.75-3.90 (m, 1H), 3.08-3.11 (m, 1H), 2.80-2.93 (m,1H), 2.28-2.41 (d, 1H), 1.95-2.10 (m, 1H), 1.84-1.95 (m, 1H), 1.70-1.84(m, 1H), 1.60-1.70 (m, 1H), 1.52 (d, 6H), 1.22-1.41 (m, 2H), 0.94-1.22(m, 2H), 0.89 (t, 1H); ESI MS m/z=456 [C₂₇H₃₃N₇+H]⁺.

Example 222 Preparation of Compound 223

Prepared by the general Suzuki coupling conditions of 62 with boronicester as shown in Scheme LXXV (58%): mp 200-206° C.; ¹H NMR (300 MHz,(CD₃)₂SO) δ 7.22-8.00 (m, 9H), 6.10 (m, 2H), 4.40-4.76 (m, 4H), 3.63 (m,1H), 1.62-2.01 (m, 7H), 1.35-1.60 (d, 6H), 1.08-1.35 (m, 4H); ESI MSm/z=527 [C₃₀H₃₈N₈O+H]⁺.

Example 223 Preparation of Compound 224

Prepared by the general Suzuki coupling conditions of 61 and3,4-dimethylbenzeneboronic acid: ¹H NMR (300 MHz, CDCl₃) δ 7.53 (m, 3H),7.41 (d, 2H), 7.26-7.38 (m, 2H), 7.19 (d, 1H), 4.79 (s, 2H), 4.64 (m,1H), 3.80 (m, 1H), 3.12 (m, 1H), 2.10-2.36 (m, 10H), 1.43-1.72 (m, 8H),1.27 (m, 4H); ESI MS m/z=484 [C₂₉H₃₇N₇+H]⁺.

Example 224 Preparation of 5-Bromo-2-cyanopyridine

2,5-Dibromopyridine (20.0 g, 84.4 mmol) was dissolved indimethylformamide (422 mL). To the stirred solution was added copper(I)cyanide. After refluxing for 5 h, the mixture was cooled to roomtemperature and stored overnight. The reaction mixture was diluted withethyl acetate (1200 mL) and filtered through a Buchner funnel containingsand, Celite, and silica gel layers. The filtrate was concentrated to avolume of 400 mL. This organic liquid was diluted with water (300 mL)and the resulting liquid was extracted with ethyl acetate (2×200 mL).The organic extracts were combined, washed with water (2×300 mL) andbrine (1×250 mL), and dried over magnesium sulfate. After concentration,the product was purified via silica gel chromatography (50:50 ethylacetate/CH₂Cl₂) to afford the title compound (9.79 g).

Example 225 Preparation of Compound 225

Prepared by reation of 5-bromo-2-cyanopyridine with benzeneboronic acidunder standard Suzuki conditions (68%).

Example 226 Preparation of Compound 226

In a Parr shaker vessel were combined 225 (300 mg, 1.67 mmol), glacialacetic acid (25 mL), and 10% palladium on carbon catalyst (177 mg, 0.167mmol). The solution was agitated under 45 psig hydrogen gas for 2 h. Theresulting dispersion was filtered through a Buchner funnel. The filtratewas concentrated. Purification by acid/base extraction yielded 226 (240mg, 78%).

Example 227 Preparation of Compound 229

Following the general schemes outlined above, compound 226 wastransformed into 227 (57% yield). Compound 227 was then transformed into228 in 83% yield. Compound 228 was then converted into compound 229 andthen its HCl salt (75%): ¹H NMR (300 MHz, CD₃OD) δ 9.11 (s, 1H), 8.90(d, 2H), 8.23 (d, 1H), 7.83 (m, 2H), 7.58 (m, 3H), 5.23 (m, 2H),4.70-5.01 (m, 1H), 3.72 (m, 1H), 3.09 (m, 1H), 1.80-2.15 (m, 4H),1.20-1.80 (m, 10H); ESI MS m/z=457 [C₂₆H₃₂N₈+H]⁺.

Example 228 Preparation of Compound 230

In a flask immersed in an ice water bath were combined 187 (30.0 mg,0.055 mmol), BOC-L-alanine (10.4 mg, 0.055 mmol), HATU (25.0 mg, 0.066mmol), N,N-diisopropylethylamine (0.050 mL, 0.274 mmol), anddimethylformamide (0.500 mL) for 10 min then warmed to room temperature.After stirring overnight, the reaction mixture was diluted withmethylene chloride (50 mL). The organic material was washed with 1 Mcitric acid (2×50 mL), saturated sodium bicarbonate solution (50 mL),and brine (50 mL). The organic layer was dried over magnesium sulfate,filtered, and concentrated in vacuo. To remove remainingdimethylformamide, the resulting material was dissolved in ethyl acetate(50 mL) and rinsed with 5% lithium chloride solution (3×50 mL). Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated in vacuo to yield 230 (28.0 mg, 79%): ¹H NMR (300 MHz,CDCl₃) δ 8.71 (s, 1H), 7.62-7.83 (m, 4H), 7.37-7.60 (m, 2H), 7.11 (m,1H), 6.11 (brs, 1H), 6.00 (d, 1H), 5.01 (brs, 1H), 4.81 (d, 2H), 4.64(m, 2H), 4.08 (m, 1H), 3.72 (m, 2H), 2.12 (m, 2H), 2.00 (m, 2H), 1.54(d, 6H), 1.43 (s, 9H), 1.15-1.38 (m, 7H); ESI MS m/z=646[C₃₄H₄₄FN₉O₃+H]⁺.

Example 229 Preparation of Compound 231

To a stirred solution of 230 in methylene chloride (2 mL) was added HClin ethanol (2 mL). After stirring for 10 min, the solution wasconcentrated in vacuo to yield 231 (15.4 mg): ¹H NMR (300 MHz, CD₃OD) δ8.92 (s, 1H), 8.35-8.67 (m, 2H), 8.32 (d, 1H), 7.83 (t, 2H), 7.69 (m,1H), 7.40 (m, 1H), 4.65-5.20 (m, 3H), 3.60-4.00 (m, 2H), 1.80-2.30 (m,4H), 2.65 (d, 3H), 1.08-1.58 (m, 12H); ESI MS m/z=546 [C₂₉H₃₆FN₉O+H]⁺.

Example 230 Preparation of Compound 232

In a flask immersed in an ice water bath were combined 187 (30.0 mg,0.055 mmol), BOC-glycine (9.6 mg, 0.055 mmol), HATU (25.0 mg, 0.066mmol), N,N-diisopropylethylamine (0.05 mL, 0.274 mmol), anddimethylformamide (0.50 mL) for 10 min then warmed to room temperature.After stirring overnight, the reaction mixture was diluted withmethylene chloride (50 mL). The organic material was washed with 1 Mcitric acid (2×50 mL), saturated sodium bicarbonate solution (50 mL),and brine (50 mL). The organic layer was dried over magnesium sulfate,filtered, and concentrated in vacuo. To remove remainingdimethylformamide, the resulting material was dissolved in ethyl acetate(50 mL) and rinsed with 5% lithium chloride solution (3×50 mL). Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated in vacuo to yield 232 (33.0 mg): ¹H NMR (300 MHz, CDCl₃) δ8.65 (s, 1H), 7.52-7.75 (m, 4H), 7.44 (s, 1H), 7.35 (q, 1H), 7.01 (t,1H), 6.05 (brs, 1H), 4.75 (d, 2H), 4.57 (m, 2H), 3.70 (m, 2H), 2.05 (m,2H), 1.92 (m, 2H), 1.46 (d, 6H), 1.40 (s, 9H), 1.20 (m, 6H); ESI MSm/z=632 [C₃₃H₄₂FN₉O₃+H]⁺.

Example 231 Preparation of Compound 233

To a stirred solution of 232 in methylene chloride (2 mL) was added HClin ethanol (2 mL). After stirring for 10 min, the solution wasconcentrated in vacuo to yield 233 (10.6 mg): ¹H NMR (300 MHz, CD₃OD) δ8.95 (s, 1H), 8.28-8.75 (m, 3H), 7.79 (t, 2H), 7.69 (m, 1H), 7.46 (t,1H), 4.63-5.20 (m, 3H), 3.59-3.92 (m, 2H), 1.96-2.24 (m, 4H), 1.62 (d,6H), 1.05-1.52 (m, 8H); ESI MS m/z=532 [C₂₈H₃₄FN₉O+H]⁺.

Example 232 Preparation of Compound 239

Reaction of 234 with 1 under standard conditions provides 236 (90%).Reaction of 236 with trans-1,4-cyclohexanediamine provides 237 (95%).Boc protection of 237 followed by Suzuki coupling provides 238 in 50%yield. Compound 238 was added to a 1:1 mixture of methylene chloride andtrifluroacetic acid. After stirring for 2 h, the solution wasconcentrated in vacuo. The resulting material was purified via silicagel chromatography (94:5:1 CH₂Cl₂:MeOH:NH₄OH) to afford 239: ¹H NMR (300MHz, CDCl₃) δ 7.51-7.61 (m, 4H), 7.48 (s, 1H), 7.41 (t, 2H), 7.31 (m,3H), 5.61 (m, 1H), 4.63 (m, 2H), 3.87 (m, 2H), 3.18 (m, 1H), 3.00 (t,2H), 2.20-2.35 (m, 3H), 1.72 (m, 4H), 1.52 (d, 6H), 1.25 (m, 4H).

Example 233 Preparation of Compound 240

Compound 239 was acetylated under the general conditions described aboveto provide 240 (73%). Salt formation occurred in 71% yield: ¹H NMR (300MHz, CDCl₃) δ 7.28-7.62 (m, 10H), 5.67 (m, 1H), 4.64 (m, 2H), 3.68-3.97(m, 3H), 3.00 (t, 2H), 2.23 (m, 2H), 1.84-2.11 (m, 7H), 1.53 (d, 6H),1.30 (m, 4H).

Example 234 Preparation of Compound 241

Reductive amination of 239 with propionaldehyde followed by saltformation provided 241: ESI MS m/z=512 [C₃₁H₄₁N₇+H]⁺.

Example 235 Preparation of Compound 242

Compound 237 was Boc-protected and then treated with 3-thiopheneboronicacid under standard Suzuki condition to prepare 242: ¹H NMR (300 MHz,CDCl₃) δ 7.33-7.76 (m, 6H), 7.28 (m, 2H), 5.72 (brs, 1H), 4.64 (m, 1H),4.43 (m, 1H), 3.83 (m, 2H), 3.47 (m, 1H), 2.97 (t, 2H), 2.21 (m, 2H),2.08 (m, 2H), 1.53 (d, 6H), 1.46 (s, 9H), 1.29 (m, 4H); ESI MS m/z=576[C₃₁H₄₁N₇O₂S+H]⁺.

Example 236 Preparation of Compound 243

Compound 242 was deprotected with HCl in methanol to provide 243: ¹H NMR(500 MHz, CDCl₃) δ 7.68 (m, 1H), 7.54 (d, 2H), 7.47 (s, 1H), 7.42 (s,1H), 7.37 (s, 1H), 7.28 (m, 2H), 5.68 (brs, 1H), 4.63 (m, 2H), 3.85 (m,3H), 2.99 (t, 2H), 2.71 (m, 1H), 2.18 (d, 2H), 1.90 (d, 2H), 1.52 (d,6H), 1.25 (m, 4H).

Example 237 Preparation of Compound 245

To a stirred solution of sodium hydride (423 mg, 17.6 mmol) intetrahydrofuran (12 mL), was added 4-phenylphenol (2.00 g, 11.8 mmol).After 1 h, BOC-2-aminoethylbromide (3.90 g, 17.6 mmol) was added to thesolution. After stirring overnight, the reaction mixture was quenchedwith 2 N potassium hydroxide solution (10 mL). The resulting mixture wasextracted with methylene chloride (12 mL). The organic layer wasconcentrated and the crude material was purified via silica gelchromatography to yield 245.

Example 238 Preparation of Compound 246

The protected amine 245 was added to 10 mL of an 1:1 mixture ofmethylene chloride and trifluoroacetic acid. After concentration, thematerial was diluted with 2 N potassium hydroxide solution (10 mL). Theaqueous layer was extracted with methylene chloride (2×10 mL). Theorganic extracts were combined, dried over magnesium sulfate, andconcentrated in vacuo to afford the product (400 mg). Reaction with 1under standard conditions provided 246 (91%).

Example 239 Preparation of Compound 248

Compound 246 was transformed into 247 under standard conditions (80%).Reaction of 247 with trans-1,4-cyclohexanediamine provided 248. Saltformation provided the target compound (68%): ¹H NMR (500 MHz, CDCl₃) δ7.53 (m, 4H), 7.40 (m, 2H), 7.29 (m, 2H), 7.00 (d, 2H), 5.93 (brs, 1H),4.61 (m, 2H), 4.22 (t, 2H), 4.02 (m, 2H), 3.78 (m, 1H), 2.70 (m, 1H),2.18 (d, 2H), 1.90 (d, 2H), 1.53 (d, 6H), 1.25 (m, 4H).

Example 240 Preparation of Compound 250

Reductive amination of 248 with propionaldehyde and salt formation understandard conditions described above provided 250: ESI MS m/z=528[C₃₁H₄₁N₇O+H]⁺.

Example 241 Preparation of Compound 249

N-Acetylation of 248 and salt formation under standard conditionsprovided 249: ¹H NMR (300 MHz, CDCl₃) δ 6.95-7.60 (m, 10H), 5.97 (brs,1H), 5.24 (d, 1H), 4.63 (m, 2H), 4.23 (t, 2H), 4.02 (m, 2H), 3.78 (m,2H), 2.21 (m, 2H), 2.04 (m, 2H), 1.94 (s, 3H), 1.55 (d, 6H), 1.30 (m,4H).

Example 242 Preparation of Compound 255

Utilizing reaction conditions described in general above, 251 wasconverted to 252 (100%). Compound 252 was converted to 253 then 254 andthen Boc-protected to make 255 (21%).

Example 243 Preparation of Compound 256

Compound 255 was treated with phenylboronic acid under standard Suzukicondions. The product was dissolved in methanol and immersed in an icewater bath. Hydrogen chloride gas was bubbled through the solution. Thesolution was concentrated in vacuo and the resulting material waspurified via preparatory HPLC (acetonitrile/water/trifluoroacetic acid)to yield 256 (8 mg).

Example 244 Preparation of Compound 257

Compound 255 was treated with 3-thiopheneboronic acid under standardSuzuki conditions. The product was dissolved in methanol and immersed inan ice water bath. Hydrogen chloride gas was bubbled through thesolution. The solution was concentrated in vacuo and the resultingmaterial was purified via preparatory HPLC(acetonitrile/water/trifluoroacetic acid) to yield 257: ¹H NMR (300 MHz,CDCl₃) δ 7.31-7.58 (m, 8H), 5.99 (brs, 1H), 5.10-5.50 (m, 1H), 4.49-4.69(m, 2H), 3.67 (m 1H), 2.67 (m, 1H), 2.13 (m, 2H), 1.90 (m, 2H), 1.62 (d,3H), 1.53 (d, 6H), 1.21 (m, 4H).

Example 245 Preparation of Compound 258

Reaction of 75 with propionoyl chloride under standard conditionsprovides 258 (89%): mp 182-183° C.

Example 246 Preparation of Compound 259

Reaction of 75 with methyl chloroformate under standard conditionsprovides 259 (68%): mp 148-150° C.

Example 247 Preparation of Compound 260

Reaction of 75 with methanesulfonyl chloride under standard conditionsprovides 260 (56%): mp 143-145° C.

Example 248 Preparation of Compound 261

Reaction of 75 with cyclopropanecarbonyl chloride under standardconditions provides 261 (87%): mp 196-204° C.

Example 249 Preparation of Compound 262

Compound 75 (250 mg, 0.549 mmol) and succinic anhydride (60.0 mg, 0.600mmol) were dissolved in xylene (30 mL). A few drops of dimethylformamidewere added to the solution. After refluxing for 48 h, the mixture wasconcentrated in vacuo. The resulting material was purified via silicagel chromatography (99.5:0.5 CH₂Cl₂/MeOH) and recrystallized from CH₂Cl₂in hexanes (1:10) to yield 262 (30.0 mg, 10%): mp 141-147° C.

Example 250 Preparation of Compound 263

The amine 75 (200 mg, 0.439 mmol) was dissolved in methylene chloride(15 mL). The stirred solution was cooled to −78° C. andN,N-diisopropylethylamine (113 mg, 0.878 mmol) andtrifluromethylsulfonylchloride (81.4 mg, 0.483 mmol) were added. After30 min, the solution was warmed to room temperature. The mixture wascooled to −78° C. and another 1.10 equivalents oftrifluoromethylsulfonylchloride and 1.50 equivalents ofN,N-diisopropylethylamine were added. After warming to room temperature,the solution was concentrated. The resulting material was purified viasilica gel chromatography (99:1 CH₂Cl₂/MeOH) and recrystallization fromether in hexanes to afford 263 (60 mg, 23%): mp 131-136° C.

Example 251 Preparation of Compound 264

Prepared by standard Suzuki coupling of 61 to provide 264 (65%): mp186-190° C.

Example 252 Preparation of Compound 265

N-Acetylation of 264 under standard conditions provides 265 (37%): mp241-246° C.

Example 253 Preparation of Compound 266

Suzuki coupling of 61 with 2-chlorobenzeneboronic acid provides 266(13%): API MS m/z=490 [C₂₇H₃₂ClN₇+H]⁺.

Example 254 Description of Biological Assays

A. Immunopurification of CyctinA/cdk2 and CyclinE/cdk2 Complexes.

CyclinA/cdk2 and cyclinE/cdk2 assays were carried out with cyclin/cdkcomplexes isolated from HeLa S-3 suspension cultures. HeLa cells weregrown in spinner flasks at 37° C. in Joklik's modified minimum essentialmedia (MEM) supplemented with 7% horse serum. After growing in mediumsupplemented with 2 mM thymidine for 16-18 h, cultures were arrested atthe G1/S border and cyclinA/cdk2 and cyclinE/cdk2 were isolated fromcell lysates by immunoprecipitation with antibodies specificallydirected against each cyclin subunit. Rabbit anti-cyclinA (H-432) andthe mouse monoclonal antibody against cyclinE (HE111) were purchasedfrom Santa Cruz Biotechnology. Cells blocked at the appropriate stage ofthe cell cycle were disrupted in lysis buffer (50 mM Tris, pH 8.0, 250mM NaCl, 0.5% NP-40 plus protease and phosphatase inhibitors) andcentrifuged at 10,000×g to remove insoluble material. To isolatecyclin/cdk complexes, 1 μg of anti-cyclin antibody was incubated withlysate from 1×10⁷ cells for 0.1 h at 4° C. Protein A-coated agarosebeads were then added for 1 h to collect antibody-bound immunecomplexes. The immobilized cyclin/cdk complexes were then washed 4× withlysis buffer to reduce nonspecific protein binding. The complexes werethen washed 1× in kinase assay buffer (50 mM Tris-HCl, pH 7.4, 10 mMMgCl₂, 1 mM DTT) and aliquoted into individual assay tubes.

B. Immunopurification of CyclinB/cdk1 Complex.

HeLa cells are blocked at the G1/S border by culturing in the presenceof 2 mM thymidine for 20 h. The cells are then rinsed 3× in phosphatebuffered saline and resuspended in regular medium. After 4 h of culture,the mitotic blocker, nocodazole is added to a final concentration of 75ng/ml. Sixteen hours later, the cells are harvested by centrifugation,washed in PBS, and lysed in cold Lysis Buffer (50 mM Tris pH 8.0, 250 mMNaCl, 0.5% NP-40, 1 mM DTT, 25 μg/ml leupeptin, 25 μg/ml aprotinin, 15μg/ml benzamidine, 1 mM PMSF, 50 mM sodium fluoride, 1 mM sodiumorthovanadate) for 15 min at 1×10⁷ cells/ml. The lysate is thenclarified by centrifugation at 10,000×g for 10 min. The supernatant iscollected and diluted 1:5 with Lysis Buffer. Monoclonal antibody againstcyclinB (GNS1) is added to the supernatant to a final concentration of 5μg/ml and shaken at 4° C. for 2 h. The immune complexes are thencollected by the addition of 200 μl of protein agarose beads for 1 h.The beads are washed 4×in lysis buffer and 1× in kinase assay buffer.

C. Protein Kinase Assays and Determination of IC₅₀ Values.

CyclinA/cdk2 assays were carried out with complexes isolated from0.5×10⁶ cells. CyclinE/cdk2 assays were carried out with complexesisolated from 4×10⁶ cells. CyclinB/cdk1 assays were carried out withcomplexes isolated from 4×10⁴ cells. After centrifugation, the washbuffer was removed and the complexes resuspended in 15 μl of kinaseassay buffer (kinase wash buffer+167 μg/ml histone H1). Compounds beingtested for inhibition were added prior to the addition of [γ ³²P] ATP toa final concentration of 15 μM. The tubes were incubated at 30° C. for 5min and the reactions were stopped by the addition of an equal volume of2×SDS-PAGE sample buffer. The samples were then subjected toelectrophoresis on 10% SDS-PAGE to resolve the histone H1 from otherreaction components. The amount of radioactive phosphate transferred tohistone H1 was quantified on a Storm Phosphorimager (MolecularDynamics).

Prior to the protein kinase assay, test compounds were dissolved in DMSOat a concentration of 25 mM and were diluted to produce finalconcentrations of 0.1, 1.0, and 10.0 μM in the kinase assays. Toeliminate possible effects of differences in DMSO concentration, theDMSO was kept constant at 0.04%, including the control reaction.Duplicate assays were performed at each concentration. The activity wasplotted as the percent of activity in the absence of added test compoundversus test compound concentration. IC₅₀ values were calculated usingGraphPad Prism data analysis software.

D. Measuring the Inhibition of Cell Growth.

Growth inhibition (GI₅₀) values were measured with HeLa S-3 cellsselected for growth on plastic. The procedure was based on the protocolof Skehan et al. (Skehan, P., et al., J. Natl. Cancer Inst.,82:1107-1112 (1990), which is hereby incorporated by reference) HeLacells were plated at 2×10⁴ cells/well in 96 well plates. One day later,a control plate was fixed by addition of TCA to 5%. After five rinseswith tap water the plate was air dried and stored at 4° C. Testcompounds were added to the remaining plates at 10-fold dilutionsbetween 0.01 and 100 μM. Two days later all plates were fixed asdescribed above. Cells were then stained by the addition of 100 μl perwell of 0.4% sulforhodamine B (SRB) in 1% acetic acid for 30 min at 4°C. Wells were then quickly rinsed 5× with acetic acid (1%) and allowedto air dry. The SRB was then solubilized by the addition of 100 μl perwell of unbuffered 10 mM Tris base. Dye was quantified by measuringabsorbance at 490 nm on a Molecular Devices kinetic microplate reader.Growth at each inhibitor concentration relative to the untreated controlwas calculated according to the following equation: percentgrowth=100×(T-T₀)/(C-T₀), where T was the average optical density (OD)of the test wells after 2 days of treatment, T₀ was the average OD ofthe wells in the control plate on day 0 and C was the average OD ofuntreated wells. Plots of percent growth versus inhibitor concentrationwere used to determine the GI₅₀.

The data below shown in Table 2 summarizes the in vitro cyclin/cdkinhibition constants (IC₅₀) and growth inhibition constants (GI₅₀) ofHeLa Cells for the compounds of the current invention. Replicateexperimental results are summarized below.

TABLE 2 In Vitro Cyclin/cdk Inhibition (IC₅₀) and Growth Inhibition(GI₅₀) of HeLa Cells For Compounds of the Current Invention. GI₅₀ IC₅₀IC₅₀ IC₅₀ HeLa CyclinA/cdk2 CyclinE/cdk2 CyclinB/cdk1 Cells Compound(μM) (μM) (μM) (μM) 5 >10 12 7 5 0.4 0.6 >10 12 2 1 3 0.06 0.7 3 0.0030.9 0.5 0.001 0.2 0.1 0.02 0.0001 13 4 2 4 3 1 0.3 2 0.8 0.9 14 3 0.4 70.4 3 2 0.03 0.03 17 1 1 10 0.4 2 0.9 3 0.6 1 0.2 11 0.25 >10 9 0.4 10 20.3 0.4 25 1 4 >10 2 6 1 >10 0.4 >10 9 >1 32 2 3 — 5 5 0.9 0.7 33 >104 >10 1 13 6 2 8 0.9 34 12 5 >10 7 13 2 6 7 36 >10 >10 >10 20 >10 >1020 >10 >10 38 >10 >10 >10 0.6 >10 >10 1 0.6 40 >10 >10 >10 9 >10 >1025 > 10 43 >10 >10 >10 4 >10 >10 4 8 46 >10 6 >10 25 8 3 >10 48 22 1 >100.3 6 5 0.6 0.5 50 >10 >10 >10 3 7 9 >10 53 >10 15 >10 0.2 >10 4 0.3 0.558 11 2 12 2 4 4 0.5 0.7 60 >10 12 >10 7 0.4 >10 6 73 >50 4 >10 0.3 1412 0.5 >10 >10 0.3 >10 >10 0.5 74 5 2 6 0.2 2 3 0.01 1 2 0.05 0.03 0.0575 3 3 6 0.09 0.02 0.005 76 12 3 6 0.07 11 5 0.01 3 2 0.06 0.2 0.0477 >10 4 >10 0.15 >10 14 0.5 0.3 78 0.9 0.6 0.8 0.05 0.9 0.3 0.8 0.0250.7 0.2 0.08 0.002 79 10 2 3 0.07 0.5 0.1 0.007 1 0.08 0.004 0.480 >10 >10 >10 >100 >10 4 >10 2 86 0.9 0.4 2 0.2 0.7 0.2 0.03 0.4 0.40.01 0.6 0.03 0.01 0.2 87 4 1 5 0.07 2 0.3 0.01 0.5 0.1 0.004 0.006 0.030.006 0.001 0.0001 88 3 4 >10 0.1 >10 >10 0.05 2 5 0.04 0.005 93 0.20.09 0.9 0.3 0.3 0.1 0.08 0.3 94 0.6 0.3 0.4 0.1 0.2 0.3 0.07 0.4 95 1 14 0.08 2 0.7 0.003 0.0005 96 8 4 6 0.04 0.01 97 >10 3 10 3 98 62 >10 >10 2 2 11 99 >10 9 >10 5 100 >10 4 >10 0.6 101 3 1 4 1 0.9 0.7 1102 >10 4 — 4 103 0.6 0.2 1 0.03 0.7 0.2 0.008 0.02 0.01 104 7 1 2 0.4 81 0.2 106 11 3 — 0.3 4 1 0.1 107 1 2 — 0.4 4 0.3 108 10 >10 — 3 >10 >105 109 0.6 0.1 — 0.04 <0.0001 110 0.6 2 — 0.02 0.03 0.02 0.01 111 0.20.07 — 0.02 0.0006 112 2 2 — <0.001 0.002 0.02 0.006 0.0006 113 0.4 0.3— <0.001 0.00001 0.03 0.001 0.02 114 3 0.7 — >10 115 3 0.4 — 3116 >10 >10 — >10 > 10 117 >10 3 — 3 118 6 1 — >10 >10 123 0.2 0.04 —<0.001 <0.001 0.0001 124 2 0.8 — 0.003 <0.001 <0.0001 130 — — — >10 >10131 — — — 3 2 132 — — — 4 3 133 — — — >10 >10 134 — — — 2 3 135 — — — 43 137 — — — 0.05 0.06 0.05 139 — — — 0.2 0.07 140 — — — 1 2 142 — — —0.4 0.5 144 — — — 0.4 0.4 146 — — — 0.7 0.3 148 — — — 1 1 149 — — — 0.30.2 150 — — — 0.3 0.2 151 — — — 0.8 0.6 152 — — — 0.7 0.3 153 — — — 3 2154 — — — 0.6 0.9 155 — — — 0.5 0.8 156 — — — 3 2 157 — — — 0.4 0.5 158— — — 0.6 0.4 159 — — — 4 3 160 — — — 0.2 0.3 161 — — — 0.2 0.4 162 — —— 0.2 0.3 163 — — — 2 3 164 — — — 0.2 0.1 165 — — — 0.2 0.1 166 — — — 42 167 — — — 2 0.9 168 — — — 4 3 169 — — — 0.5 0.3 170 — — — 4 2 171 — —— 3 3 172 — — — 0.3 0.3 173 — — — 3 3 174 — — — 0.04 0.03 0.1 0.06 0.40.4 175 — — — 0.6 0.3 177 — — — 0.2 0.06 0.06 178 — — — 0.4 0.2 179 — —— 0.1 0.05 0.05 180 — — — 0.4 0.3 181 — — — 0.04 182 — — — 0.3 0.3 187 —— — 0.05 0.03 188 — — — 0.2 0.07 194 — — — 0.06 0.04 199 — — — 0.2 0.09200 — — — 0.3 0.2 206 — — — 0.2 0.2 207 — — — 0.4 0.2 208 — — — 4 3 209— — — 2 2 210 — — — 3 4 211 — — — 0.6 0.3 212 — — — 5 3 213 — — — 3 2214 — — — 5 5 215 — — — 2 3 216 — — — 0.5 0.5 217 — — — 4 4 218 — — — 35 219 — — — 0.4 0.6 221 — — — 2 2 222 — — — 1 2 223 — — — 0.04 0.1 224 —— — 2 2 229 — — — 0.4 230 — — — 0.3 231 — — — 0.04 232 — — — 0.3 233 — —— 0.5 239 — — — 4 6 240 — — — 8 8 241 — — — 7 4 242 — — — 7 >10 243 — —— 3 3 248 — — — 3 4 249 — — — >10 >10 250 — — — 3 6 256 — — — 4 3 257 —— — 3 3 258 — — — 0.2 0.3 0.4 259 — — — 0.3 0.4 0.7 260 — — — 0.2 0.10.2 261 — — — 0.3 0.3 0.3 262 — — — 0.3 0.2 0.5 263 — — — 2 3 4 264 — —— 0.3 0.3 0.5 265 — — — 0.3 0.3 0.4 266 — — — 0.3 0.3 0.5 267 — — — 0.80.6

The data below shown in Table 3 summarizes the in vitro cyclin/cdkinhibition (IC₅₀) and growth inhibition (GI₅₀) of HeLa Cells for severalreference compounds in comparison to several compounds of the currentinvention. The chemical structures are provided.

TABLE 3 In Vitro cyclin/cdk Inhibition (IC₅₀) and Growth Inhibition(GI₅₀) of HeLa Cells For Reference Compounds in Comparison to SeveralCompounds of the Current Invention. IC₅₀ IC₅₀ IC₅₀ GI₅₀ HeLaCyclinA/cdk2 CyclinE/cdk2 CyclinB/cdk1 Cells Compound Structure (μM)(μM) (μM) (μM) Olomoucine

0.5-24 (n > 10)  1-14 (n > 10) 7-23 (n > 10) 75 Roscovitine

2.1 4 3 0.04 0.7 — 30 25 30 >10 25 Flavopiridol

0.06 0.2 0.6 0.04 0.06 (n = 2) 0.18 125

1 0.1 0.6 3 126

0.6 0.8 0.06 0.06 2 0.2 2 4 6  74

5 2 6 0.2 0.01 0.05 127

0.3-2  (n > 15) 0.04-0.07 (n > 15) 0.5-2 (n > 15) 7-15 (n > 5)  88

3 4 >10 0.1 0.05 0.04The following data in Tables 4, 5, 6, and 7 summarize the growthinhibition properties of several compounds of the current invention andolomoucine against 60-human transformed cell lines. These data werecooperatively obtained at the National Cancer Institute in their 60-cellline growth inhibition assay according to published procedures (Boyd, M.R., “Anticancer Drug Development Guide,” Preclinical Screening ClinicalTrials, and Approval; Teicher, B. Ed.; Humana Press; Totowa, N.J., 23-42(1997), which is hereby incorporated by reference).

TABLE 4 In Vitro Growth Inhibition (GI₅₀) of NCI Human Transformed CellLines of Several Compounds of the Current Invention. 73 GI₅₀ 17 GI₅₀ 33GI₅₀ 38 GI₅₀ Cancer Type Cell Line (μM) (μM) (μM) (μM) Breast BT-5490.25 0.40 51.3 0.32 Breast HS 578T 0.10 6.31 — — Breast MCF7 0.16 0.165.2 0.20 Breast MDA-MB- 0.50 — — 0.06 231/ATCC Breast MDA-MB-435 0.250.20 4.9 0.05 Breast MDA-N 0.13 0.11 — — Breast NCI/ADR-RES 0.40 0.286.3 0.32 Breast T-47D 0.25 0.13 3.9 0.25 CNS SF-268 0.16 0.04 6.3 0.20CNS SF-295 0.25 0.19 7.8 0.50 CNS SF-539 0.76 0.40 89.1 1.26 CNS SNB-190.43 0.14 38.0 0.50 CNS SNB-75 0.02 0.02 — — CNS U251 0.32 0.40 3.7 0.20Colon COLO 205 0.28 0.05 7.8 0.16 Colon HCC-2998 0.20 0.03 >1000 7.94Colon HCT-116 0.20 0.16 6.2 0.32 Colon HCT-15 0.18 0.04 8.9 0.25 ColonHT29 — 0.10 8.9 0.25 Colon KM12 0.13 0.03 4.1 0.16 Colon SW-620 — 0.012.9 0.03 Leukemia CCRF-CEM 0.25 0.16 4.6 0.20 Leukemia HL-60(TB) — — 3.20.04 Leukemia K-562 0.16 0.16 3.1 0.25 Leukemia MOLT-4 0.32 0.25 3.80.25 Leukemia RPMI-8226 0.03 0.03 1.5 — Leukemia SR — 0.50 4.5 3.98Melanoma LOX IMVI — 0.32 16.6 0.40 Melanoma M14 0.03 0.03 7.8 0.05Melanoma MALME-3M 0.27 19.95 11.7 0.25 Melanoma SK-MEL-2 0.63 1.00 >10002.00 Melanoma SK-MEL-28 0.45 0.12 5.9 0.03 Melanoma SK-MEL-5 0.25 0.3216.2 0.32 Melanoma UACC-257 0.16 0.20 75.9 0.50 Melanoma UACC-62 0.300.27 8.3 1.00 Non-Small Cell A549/ATCC 0.03 0.03 4.6 0.13 Lung Non-SmallCell EKVX 0.25 2.51 6.9 0.20 Lung Non-Small Cell HOP-62 0.06 0.20 >10000.32 Lung Non-Small Cell HOP-92 1.00 1.58 — 0.32 Lung Non-Small CellNCI-H226 0.22 0.11 — — Lung Non-Small Cell NCI-H23 0.32 0.16 26.3 0.32Lung Non-Small Cell NCI-H322M 0.16 >1000 38.9 0.40 Lung Non-Small CellNCI-H460 0.40 0.41 25.7 3.16 Lung Non-Small Cell NCI-H522 — — 4.2 — LungOvarian IGROV1 0.32 0.20 10.0 0.16 Ovarian OVCAR-3 0.30 0.65 >1000 1.00Ovarian OVCAR-4 0.32 0.32 31.6 1.26 Ovarian OVCAR-5 0.25 0.26 >1000 0.40Ovarian OVCAR-8 — 0.13 6.6 0.25 Ovarian SK-OV-3 0.95 0.40 >1000 3.98Prostate DU-145 7.08 0.63 17.8 1.26 Prostate PC-3 0.35 0.20 >1000 0.40Renal 786-0 0.20 0.25 18.6 0.32 Renal A498 2.88 1.58 — 1.26 Renal ACHN0.32 0.40 5.2 2.00 Renal CAKI-1 1.66 0.13 4.4 0.20 Renal RXF 393 0.090.02 13.2 0.13 Renal SN12C — 0.56 — — Renal TK-10 — — 8.3 0.40 RenalUO-31 0.06 0.10 8.1 0.13

TABLE 5 In Vitro Growth Inhibition (GI₅₀) of NCI Human Transformed CellLines of Several Compounds of the Current Invention. 43 GI₅₀ 48 GI₅₀ 75GI₅₀ 76 GI₅₀ Cancer Type Cell Line (μM) (μM) (μM) (μM) Breast BT-549 4.00.01 <0.01 <0.01 Breast HS 578T — 0.03 <0.01 <0.01 Breast MCF7 2.7 0.25<0.01 <0.01 Breast MDA-MB- 3.2 0.09 <0.01 <0.01 231/ATCC BreastMDA-MB-435 2.1 — — — Breast MDA-N — 0.02 <0.01 <0.01 Breast NCI/ADR-RES5.2 0.12 0.48 0.015 Breast T-47D 2.2 0.15 <0.01 <0.01 CNS SF-268 3.0<0.01 <0.01 <0.01 CNS SF-295 4.0 0.24 <0.01 <0.01 CNS SF-539 3.4 0.380.02 0.054 CNS SNB-19 5.0 0.02 <0.01 <0.01 CNS SNB-75 — <0.01 <0.01<0.01 CNS U251 2.3 0.17 <0.01 0.020 Colon COLO 205 1.6 0.03 <0.01 <0.01Colon HCC-2998 3.4 — — — Colon HCT-116 2.1 0.19 <0.01 0.014 Colon HCT-153.9 0.02 0.03 <0.01 Colon HT29 3.6 <0.01 <0.01 <0.01 Colon KM12 2.3 0.02<0.01 <0.01 Colon SW-620 1.6 <0.01 <0.01 <0.01 Leukemia CCRF-CEM 2.80.03 <0.01 <0.01 Leukemia HL-60(TB) 2.1 — — — Leukemia K-562 3.1 0.16<0.01 <0.01 Leukemia MOLT-4 2.0 0.05 <0.01 <0.01 Leukemia RPMI-8226 —<0.01 <0.01 <0.01 Leukemia SR 2.2 0.16 <0.01 <0.01 Melanoma LOX IMVI 3.40.19 <0.01 <0.01 Melanoma M14 2.2 <0.01 <0.01 <0.01 Melanoma MALME-3M3.0 0.13 <0.01 <0.01 Melanoma SK-MEL-2 61.7 0.48 0.02 0.112 MelanomaSK-MEL-28 2.3 <0.01 <0.01 <0.01 Melanoma SK-MEL-5 2.1 0.17 0.01 0.013Melanoma UACC-257 4.8 0.04 <0.01 <0.01 Melanoma UACC-62 3.3 0.10 0.010.018 Non-Small Cell A549/ATCC 4.1 <0.01 <0.01 <0.01 Lung Non-Small CellEKVX 2.8 — — — Lung Non-Small Cell HOP-62 3.3 0.03 <0.01 <0.01 LungNon-Small Cell HOP-92 2.6 0.46 <0.01 0.017 Lung Non-Small Cell NCI-H226— — — — Lung Non-Small Cell NCI-H23 4.3 0.07 <0.01 <0.01 Lung Non-SmallCell NCI-H322M 3.5 0.03 <0.01 <0.01 Lung Non-Small Cell NCI-H460 3.20.25 <0.01 0.047 Lung Non-Small Cell NCI-H522 — <0.01 <0.01 <0.01 LungOvarian IGROV1 3.4 0.23 <0.01 <0.01 Ovarian OVCAR-3 9.3 0.17 <0.01 <0.01Ovarian OVCAR-4 8.9 0.20 <0.01 <0.01 Ovarian OVCAR-5 3.6 0.16 <0.01<0.01 Ovarian OVCAR-8 3.9 0.10 <0.01 <0.01 Ovarian SK-OV-3 72.4 1.380.03 0.051 Prostate DU-145 2.6 0.55 <0.01 0.043 Prostate PC-3 38.9 0.23<0.01 <0.01 Renal 786-0 3.1 0.25 <0.01 <0.01 Renal A498 3.0 0.39 0.01<0.01 Renal ACHN 3.1 0.25 0.02 0.025 Renal CAKI-1 3.0 — — — Renal RXF393 1.9 <0.01 <0.01 <0.01 Renal SN12C — 0.03 <0.01 <0.01 Renal TK-10 3.20.37 <0.01 0.013 Renal UO-31 2.8 <0.01 0.03 <0.01

TABLE 6 In Vitro Growth Inhibition (GI₅₀) of NCI Human Transformed CellLines of Several Compounds of the Current Invention. Cancer Type CellLine 79 GI₅₀ (μM) 87 GI₅₀ (μM) 12 GI₅₀ (μM) Breast BT-549 <0.01 0.020.041 Breast HS 578T <0.01 <0.01 <0.005 Breast MCF7 <0.01 0.04 <0.005Breast MDA-MB-231/ATCC <0.01 <0.01 <0.005 Breast MDA-MB-435 <0.01 <0.01<0.005 Breast MDA-N <0.01 0.014 <0.005 Breast NCI/ADR-RES 0.86 0.28 1.26Breast T-47D <0.01 0.048 0.0088 CNS SF-268 <0.01 <0.01 <0.005 CNS SF-295<0.01 0.047 0.018 CNS SF-539 <0.01 0.081 0.022 CNS SNB-19 <0.01 0.0380.016 CNS SNB-75 <0.01 0.012 <0.005 CNS U251 <0.01 0.028 0.0078 ColonCOLO 205 <0.01 <0.01 <0.005 Colon HCC-2998 <0.01 <0.01 <0.005 ColonHCT-116 <0.01 0.037 0.0089 Colon HCT-15 <0.01 0.066 0.17 Colon HT29<0.01 <0.01 <0.005 Colon KM12 <0.01 <0.01 <0.005 Colon SW-620 <0.01<0.01 <0.005 Leukemia CCRF-CEM <0.01 <0.01 <0.005 Leukemia HL-60(TB)<0.01 <0.01 <0.005 Leukemia K-562 <0.01 0.024 <0.005 Leukemia MOLT-4<0.01 0.02 <0.005 Leukemia RPMI-8226 <0.01 <0.01 <0.005 Leukemia SR<0.01 0.032 <0.005 Melanoma LOX IMVI <0.01 0.027 <0.005 Melanoma M14<0.01 <0.01 <0.005 Melanoma MALME-3M <0.01 0.024 0.010 Melanoma SK-MEL-2<0.01 0.056 0.0096 Melanoma SK-MEL-28 <0.01 <0.01 0.01 Melanoma SK-MEL-5<0.01 0.028 0.014 Melanoma UACC-257 <0.01 0.017 0.008 Melanoma UACC-62<0.01 0.045 0.027 Non-Small Cell Lung A549/ATCC <0.01 <0.01 <0.005Non-Small Cell Lung EKVX <0.01 0.081 0.023 Non-Small Cell Lung HOP-62<0.01 0.01 <0.005 Non-Small Cell Lung HOP-92 <0.01 0.088 0.011 Non-SmallCell Lung NCI-H226 <0.01 0.0.052 0.021 Non-Small Cell Lung NCI-H23 <0.010.022 <0.005 Non-Small Cell Lung NCI-H322M <0.01 0.021 <0.005 Non-SmallCell Lung NCI-H460 <0.01 0.22 0.015 Non-Small Cell Lung NCI-H522 <0.01<0.01 <0.005 Ovarian IGROV1 <0.01 0.052 0.013 Ovarian OVCAR-3 <0.01 0.050.012 Ovarian OVCAR-4 <0.01 0.048 <0.005 Ovarian OVCAR-5 <0.01 0.0510.017 Ovarian OVCAR-8 <0.01 0.033 0.0076 Ovarian SK-OV-3 <0.01 0.350.018 Prostate DU-145 <0.01 0.22 0.017 Prostate PC-3 <0.01 0.018 <0.005Renal 786-0 <0.01 0.047 0.0065 Renal A498 <0.01 0.10 0.016 Renal ACHN<0.01 0.19 0.039 Renal CAKI-1 <0.01 0.064 0.038 Renal RXF 393 <0.010.011 <0.005 Renal SN12C <0.01 <0.01 <0.005 Renal TK-10 <0.01 0.029 0.01Renal UO-31 <0.01 0.016 0.063

TABLE 7 In Vitro Growth Inhibition (GI₅₀) of NCI Human Transformed CellLines of Several Compounds of the Current Invention and Olomoucine.Cancer 74 GI₅₀ 78 GI₅₀ 77 GI₅₀ Olomoucine Type Cell Line (μM) (μM) (μM)GI₅₀ (μM) Breast BT-549 0.16 0.04 <0.01 79 Breast HS 578T <0.01 — <0.0163 Breast MCF7 <0.01 <0.01 0.03 50 Breast MDA-MB- <0.01 <0.01 0.04 100231/ATCC Breast MDA-MB-435 — — — 63 Breast MDA-N <0.01 <0.01 0.01 79Breast NCI/ADR-RES 0.24 14.45 0.03 100 Breast T-47D <0.01 0.03 0.01 63CNS SF-268 <0.01 — <0.01 50 CNS SF-295 <0.01 0.21 0.04 79 CNS SF-5390.07 — 0.22 32 CNS SNB-19 <0.01 <0.01 0.03 63 CNS SNB-75 <0.01 <0.01<0.01 25 CNS U251 <0.01 0.02 0.09 50 Colon COLO 205 <0.01 <0.01 0.02 32Colon HCC-2998 — <0.01 — 63 Colon HCT-116 <0.01 0.03 0.05 40 ColonHCT-15 <0.01 1.48 <0.01 40 Colon HT29 <0.01 <0.01 <0.01 63 Colon KM12<0.01 <0.01 <0.01 40 Colon SW-620 <0.01 <0.01 <0.01 40 Leukemia CCRF-CEM<0.01 — <0.01 40 Leukemia HL-60(TB) — <0.01 — 40 Leukemia K-562 <0.010.02 0.02 100 Leukemia MOLT-4 <0.01 <0.01 0.01 63 Leukemia RPMI-8226<0.01 <0.01 <0.01 50 Leukemia SR <0.01 — 0.02 25 Melanoma LOX IMVI <0.01— 0.04 32 Melanoma M14 <0.01 <0.01 <0.01 100 Melanoma MALME-3M 0.01 0.010.05 100 Melanoma SK-MEL-2 0.06 0.02 0.51 100 Melanoma SK-MEL-28 <0.010.01 <0.01 50 Melanoma SK-MEL-5 0.06 0.10 0.08 40 Melanoma UACC-257<0.01 0.02 0.02 79 Melanoma UACC-62 0.04 0.03 0.12 32 Non-SmallA549/ATCC <0.01 <0.01 <0.01 50 Cell Lung Non-Small EKVX — 0.05 — 100Cell Lung Non-Small HOP-62 <0.01 0.02 <0.01 32 Cell Lung Non-SmallHOP-92 0.03 — 0.13 50 Cell Lung Non-Small NCI-H226 — 0.02 — 50 Cell LungNon-Small NCI-H23 <0.01 0.01 0.01 79 Cell Lung Non-Small NCI-H322M <0.01<0.01 <0.01 63 Cell Lung Non-Small NCI-H460 <0.01 0.05 0.22 63 Cell LungNon-Small NCI-H522 <0.01 <0.01 <0.01 40 Cell Lung Ovarian IGROV1 <0.01<0.01 0.09 40 Ovarian OVCAR-3 <0.01 0.03 0.02 79 Ovarian OVCAR-4 <0.010.02 <0.01 100 Ovarian OVCAR-5 0.03 <0.01 0.04 40 Ovarian OVCAR-8 <0.010.02 0.02 63 Ovarian SK-OV-3 0.22 0.06 0.19 100 Prostate DU-145 0.020.06 0.13 40 Prostate PC-3 <0.01 <0.01 0.02 100 Renal 786-0 <0.01 0.040.03 63 Renal A498 0.03 0.03 0.03 32 Renal ACHN 0.03 0.32 0.11 25 RenalCAKI-1 — 0.79 — 32 Renal RXF 393 <0.01 <0.01 <0.01 20 Renal SN12C <0.01<0.01 <0.01 100 Renal TK-10 <0.01 0.07 0.05 63 Renal UO-31 0.01 0.17<0.01 32The following data in Table 8 summarize the in vivo properties ofseveral compounds of the current invention. These data werecooperatively obtained at the National Cancer Institute in their HollowFiber Assay according to published procedures (Hollingshead, M. G., etal “In Vivo Cultivation of Tumor Cells in Hollow Fibers,” Life Sciences,1995, 57(2), 131-141 which is hereby incorporated by reference).

TABLE 8 In Vivo Evaluation of Several Compounds of the CurrentInvention. Com- MTD IP SC Cell pound (mg/kg) Score score Kill Cell TypesKilled 73 100 2 0 N — 17 100 8 0 Y H522 38 100 0 4 N — 78 6.3 34 0 YH23, H522, OVCAR3, SF29 79 6.3 26 6 N — 86 6.3 38 0 Y OVCAR 3, OVCAR 5,H522 87 25 30 2 Y H522 12 3.1 26 4 Y H522, MDA-MB-435 93 25 22 8 YOVCAR-3 94 50 22 2 Y COLO205, OVCAR-3, H522 103 6.3 38 6 Y OVCAR 3,OVCAR 5, H522, MDA-MB-435, SF295 109 400 18 10 Y H522 112 50 18 2 YOVCAR-3 113 200 18 4 Y H23, H522, OVCAR-3 110 50 14 0 Y OVCAR-3 124 2528 0 Y H23, H522, OVCAR-3, MDA-MB-435

The following data in Table 9 summarize the in vivo properties ofseveral compounds of the current invention. The protocol for theexperiment is as follows. The dose-range finding study consists of fourgroups of three athymic mice each (four dose levels.) The compound isadministered on the basis of individual animal body weight. The route isintraperitoneal (IP) and the treatment schedule is daily for 14 days(qd×14) or once every 4 days for 12 days (q4d×3). The mice were observedfor survival, and body weights recorded weekly.

The efficacy study consists of three compound-treated groups (sixmice/group), a positive control-treated group (six mice), and avehicle-treated control group of 12 mice. Test compounds wereadministered IP under the treatment schedules listed above (qd×14 orq4d×3), whereas the positive control agent (Taxol) was administeredintravenously (IV) at a dosage level of 15 mg/1 g/dose for fiveconsecutive days (qd×5). All agents were administered on the basis ofindividual animal body weight. Treatment began when the implanted tumorswere approximately 100 mg in size (range of 65 to 200 mg). The mice wereobserved daily for survival. Each tumor was measured by caliper in twodimensions and converted to tumor mass using the formula for a prolateellipsoid (a×b²/2) and assuming unit density. Tumor measurements andanimal body weights were recorded twice weekly. Antitumor activity wasassessed by the delay in tumor growth of the treated groups incomparison to the vehicle-treated control group, partial and completeregressions, and tumor-free survivors.

TABLE 9 In Vivo Evaluation of Several Compounds of the CurrentInvention. Tumor Compound Dose (mg/kg) Route Schedule free/total T-C(days) 78 0.5 IP qd × 14 0/6 0.8 78 0.33 IP qd × 14 0/6 1.8 78 0.22 IPqd × 14 0/6 −0.8 78 1.5 IP q4d × 3 0/6 2.5 78 1.0 IP q4d × 3 0/6 1.1 780.67 IP q4d × 3 0/6 2.0 12 0.6 IP q4d × 3 0/6 0.3 12 0.4 IP q4d × 3 0/60.2 12 0.27 IP q4d × 3 0/6 1.2 87 15 IP q4d × 3 0/6 2.5 87 10 IP q4d × 30/6 2.9 87 6.7 IP q4d × 3 0/6 1.4

Although the invention has been described in detail for the purpose ofillustration, it is understood that such detail is solely for thatpurpose, and variations can be made therein by those skilled in the artwithout departing from the spirit and scope of the invention which isdefined by the following claims.

1. A compound of the following formula:

wherein: R₁ are the same or different and independently selected fromthe group consisting of: H; C₁-C₆-straight chain alkyl; C₂-C₆-straightalkenyl chain; C₃-C₆-branched alkyl chain; C₃-C₆-branched alkenyl chain;C₃-C₇-cycloalkyl; CH₂—(C₃-C₇-cycloalkyl); CH₂CF₃; CH₂CH₂CF₃; andCH(CF₃)₂; Q=N and D=X=CH; V=NH; O; S; or CH₂; R₂=phenyl; substitutedphenyl, wherein the substituents (1-2 in number) are in any position andare independently selected from the group consisting of R₁, OR₁, SR₁,S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁,C(O)NHR₁, phenyl, and C(O)NHCHR₁CH₂OH; 1-naphthyl; 2-naphthyl;heterocycles selected from the group consisting of: 2-pyridyl;3-pyridyl; 4-pyridyl; 2-pyrimidyl; 4-pyrimidyl; 5-pyrimidyl;thiophene-2-yl; thiophene-3-yl; 2-furanyl; 3-furanyl; oxazol-2-yl;oxazol-4-yl; oxazol-5-yl; thiazol-2-yl; thiazol-4-yl; thiazol-5-yl;imidazol-2-yl; imidazol-4-yl; pyrazol-3-yl; pyrazol-4-yl; isoxazol-3-yl;isoxazol-4-yl; isoxazol-5-yl; isothiazol-3-yl; isothiazol-4-yl;isothiazol-5-yl; 1,3,4-thiadiazol-2-yl; benzo[b]furan-2-yl;benzo[b]thiophene-2-yl; 2-pyrrolyl; 3-pyrrolyl; 1,3,5-triazin-2-yl;pyrazin-2-yl; pyridazin-3-yl; pyridazin-4-yl; 2-quinolinyl;3-quinolinyl; 4-quinolinyl; 1-isoquinolinyl; 3-isoquinolinyl; and4-isoquinolinyl; or substituted heterocycle, wherein the substituents(1-2 in number) are in any position and are independently selected fromthe group consisting of Br, Cl, F, R₁, and C(O)CH₃; R₃ are the same ordifferent and independently selected from the group consisting of: H;C₁-C₄-straight chain alkyl; C₃-C₄-branched chain alkyl; C₂-C₄-alkenylchain; (CH₂)_(n)Ph; and (CH₂)_(n)-substituted phenyl, wherein the phenylsubstituents are as defined above in R₂; R₄=H; C₁-C₄-straight chainalkyl; or C₃-C₄-branched chain alkyl; R₃ and R₄ can be linked togetherby a carbon chain to form with intervening atoms a 5-8-memberedsaturated or unsaturated ring; n₁=0-3; n=0-3; A=CH₂; (CH₂)₂; (CH₂)₃;OCH₂CH₂; or CHCH₃; Y=H; OR₁; N(R₁)₂; N(R₁)C(O)R₃; N(R₁)C(O)R₅;N(R₁)C(O)CH(R₆)NH₂; N(R₁)SO₂R₃; N(R₁)C(O)NHR₃; or N(R₁)C(O)OR₆;R₅=C₃-C₇-cycloalkyl; R₆=C₁-C₄-straight chain alkyl; C₃-C₄-branched chainalkyl; C₂-C₄-alkenyl chain; (CH₂)_(n)Ph; or (CH₂)_(n)-substitutedphenyl, wherein the phenyl substituents are as defined above in R₂; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein R₃ are the same or different and independently selectedfrom the group consisting of: H; C₁-C₄-straight chain alkyl; andC₃-C₄-branched chain alkyl; Y=H; OR₁; N(R₁)₂; N(R₁)C(O)R₃; N(R₁)SO₂R₃;or N(R₁)C(O)NHR₃.
 3. A compound of the following formula:

wherein: R₁ are the same or different and independently selected fromthe group consisting of: H; C₁-C₆-straight chain alkyl; C₂-C₆-straightalkenyl chain; C₃-C₆-branched alkyl chain; C₃-C₆-branched alkenyl chain;C₃-C₇-cycloalkyl; CH₂—(C₃-C₇-cycloalkyl); CH₂CF₃; CH₂CH₂CF₃; andCH(CF₃)₂; Q=N and D=X=CH; V=NH; O; S; or CH₂; R₂=phenyl; substitutedphenyl, wherein the substituents (1-2 in number) are in any position andare independently selected from the group consisting of R₁, OR₁, SR₁,S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁,C(O)NHR₁, phenyl, and C(O)NHCHR₁CH₂OH; 1-naphthyl; 2-naphthyl;heterocycles selected from the group consisting of: 2-pyridyl;3-pyridyl; 4-pyridyl; 2-pyrimidyl; 4-pyrimidyl; 5-pyrimidyl;thiophene-2-yl; thiophene-3-yl; 2-furanyl; 3-furanyl; oxazol-2-yl;oxazol-4-yl; oxazol-5-yl; thiazol-2-yl; thiazol-4-yl; thiazol-5-yl;imidazol-2-yl; imidazol-4-yl; pyrazol-3-yl; pyrazol-4-yl; isoxazol-3-yl;isoxazol-4-yl; isoxazol-5-yl; isothiazol-3-yl; isothiazol-4-yl;isothiazol-5-yl; 1,3,4-thiadiazol-2-yl; benzo[b]furan-2-yl;benzo[b]thiophene-2-yl; 2-pyrrolyl; 3-pyrrolyl; 1,3,5-triazin-2-yl;pyrazin-2-yl; pyridazin-3-yl; pyridazin-4-yl; 2-quinolinyl;3-quinolinyl; 4-quinolinyl; 1-isoquinolinyl; 3-isoquinolinyl; and4-isoquinolinyl; or substituted heterocycle, wherein the substituents(1-2 in number) are in any position and are independently selected fromthe group consisting of Br, Cl, F, R₁, and C(O)CH₃; n=0-3; A=CH₂;(CH₂)₂; (CH₂)₃; OCH₂CH₂; or CHCH₃; Y=H; OR₁; N(R₁)₂; N(R₁)C(O)R₃;N(R₁)C(O)R₅; N(R₁)C(O)CH(R₆)NH₂; N(R₁)SO₂R₃; N(R₁)C(O)NHR₃; orN(R₁)C(O)OR₆; R₃ are the same or different and independently selectedfrom the group consisting of: H; C₁-C₄-straight chain alkyl;C₃-C₄-branched chain alkyl; C₂-C₄-alkenyl chain; (CH₂)_(n)Ph; and(CH₂)_(n)-substituted phenyl, wherein the phenyl substituents are asdefined above in R₂; R₅=C₃-C₇-cycloalkyl; R₆=C₁-C₄-straight chain alkyl;C₃-C₄-branched chain alkyl; or C₂-C₄-alkenyl chain; or apharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition of matter comprising the compound of claim 1 and one or morepharmaceutical excipients.
 5. A pharmaceutical composition of mattercomprising the compound of claim 3 and one or more pharmaceuticalexcipients.
 6. A process for preparation of a purine derivative compoundof the formula:

wherein: R₁ are the same or different and independently selected fromthe group consisting of: H; C₁-C₆-straight chain alkyl; C₂-C₆-straightalkenyl chain; C₃-C₆-branched alkyl chain; C₃-C₆-branched alkenyl chain;C₃-C₇-cycloalkyl; CH₂—(C₃-C₇-cycloalkyl); CH₂CF₃; CH₂CH₂CF₃; andCH(CF₃)₂; Q=N and D=X=CH; V=NH; O; S; or CH₂; R₂=phenyl; substitutedphenyl, wherein the substituents (1-2 in number) are in any position andare independently selected from the group consisting of R₁, OR₁, SR₁,S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁,C(O)NHR₁, phenyl, and C(O)NHCHR₁CH₂OH; 1-naphthyl; 2-naphthyl;heterocycles selected from the group consisting of: 2-pyridyl;3-pyridyl; 4-pyridyl; 2-pyrimidyl; 4-pyrimidyl; 5-pyrimidyl;thiophene-2-yl; thiophene-3-yl; 2-furanyl; 3-furanyl; oxazol-2-yl;oxazol-4-yl; oxazol-5-yl; thiazol-2-yl; thiazol-4-yl; thiazol-5-yl;imidazol-2-yl; imidazol-4-yl; pyrazol-3-yl; pyrazol-4-yl; isoxazol-3-yl;isoxazol-4-yl; isoxazol-5-yl; isothiazol-3-yl; isothiazol-4-yl;isothiazol-5-yl; 1,3,4-thiadiazol-2-yl; benzo[b]furan-2-yl;benzo[b]thiophene-2-yl; 2-pyrrolyl; 3-pyrrolyl; 1,3,5-triazin-2-yl;pyrazin-2-yl; pyridazin-3-yl; pyridazin-4-yl; 2-quinolinyl;3-quinolinyl; 4-quinolinyl; 1-isoquinolinyl; 3-isoquinolinyl; and4-isoquinolinyl; or substituted heterocycle, wherein the substituents(1-2 in number) are in any position and are independently selected fromthe group consisting of Br, Cl, F, R₁, and C(O)CH₃; R₃ are the same ordifferent and independently selected from the group consisting of: H;C₁-C₄-straight chain alkyl; C₃-C₄-branched chain alkyl; C₂-C₄-alkenylchain; (CH₂)_(n)Ph; and (CH₂)_(n)-substituted phenyl, wherein the phenylsubstituents are as defined above in R₂; R₄=H; C₁-C₄-straight chainalkyl; or C₃-C₄-branched chain alkyl; R₃ and R₄ can be linked togetherby a carbon chain to form with intervening atoms a 5-8-memberedsaturated or unsaturated ring; n₁=0-3; n=0-3; A=CH₂; (CH₂)₂; (CH₂)₃;OCH₂CH₂; or CHCH₃; Y=H; OR₁; N(R₁)₂; N(R₁)C(O)R₃; N(R₁)C(O)R₅;N(R₁)C(O)CH(R₆)NH₂; N(R₁)SO₂R₃; N(R₁)C(O)NHR₃; or N(R₁)C(O)OR₃(;R₅=C₃-C₇-cycloalkyl; R₆=C₁-C₄-straight chain alkyl; C₃-C₄-branched chainalkyl; C₂-C₄-alkenyl chain; (CH₂)_(n)Ph; or (CH₂)_(n)-substitutedphenyl, wherein the phenyl substituents are as defined above in R₂; or apharmaceutically acceptable salt thereof; said process comprising:reacting a first intermediate compound of the formula:

where Z=Br or I with a compound of the formula: R₂—B(OH)₂, R₂—Sn(n-Bu)₃,or R₂—Sn(Me)₃, or mixtures thereof, under conditions effective to formthe purine derivative compound.
 7. A process according to claim 6,wherein if Y is NHR₁, said process further comprises: reacting thepurine derivative compound with R₃C(O)C₁ or R₅C(O)C₁ or R₃SO₂C₁ or R₃NCOor R₆OC(O)Cl under conditions effective to form a final product havingthe same formula as the purine derivative compound except that Y isNR₁C(O)R₃ or NR₁C(O)R₅ or NR₁SO₂R₃ or NR₁C(O)NHR₃ or NR₁C(O)OR₆.
 8. Aprocess for preparation of a purine derivative compound of the formula:

wherein: R₁ are the same or different and independently selected fromthe group consisting of: H; C₁-C₆-straight chain alkyl; C₂-C₆-straightalkenyl chain; C₃-C₆-branched alkyl chain; C₃-C₆-branched alkenyl chain;C₃-C₇-cycloalkyl; CH₂—(C₃-C₇-cycloalkyl); CH₂CF₃; CH₂CH₂CF₃; andCH(CF₃)₂; Q=N, and D=X=CH; V=NH; O; or S; R₂=phenyl; substituted phenyl,wherein the substituents (1-2 in number) are in any position and areindependently selected from the group consisting of R₁, OR₁, SR₁,S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁,C(O)NHR₁, phenyl, and C(O)NHCHR₁CH₂OH; 1-naphthyl; 2-naphthyl;heterocycles selected from the group consisting of: 2-pyridyl;3-pyridyl; 4-pyridyl; 2-pyrimidyl; 4-pyrimidyl; 5-pyrimidyl;thiophene-2-yl; thiophene-3-yl; 2-furanyl; 3-furanyl; oxazol-2-yl;oxazol-4-yl; oxazol-5-yl; thiazol-2-yl; thiazol-4-yl; thiazol-5-yl;imidazol-2-yl; imidazol-4-yl; pyrazol-3-yl; pyrazol-4-yl; isoxazol-3-yl;isoxazol-4-yl; isoxazol-5-yl; isothiazol-3-yl; isothiazol-4-yl;isothiazol-5-yl; 1,3,4-thiadiazol-2-yl; benzo[b]furan-2-yl;benzo[b]thiophene-2-yl; 2-pyrrolyl; 3-pyrrolyl; 1,3,5-triazin-2-yl;pyrazin-2-yl; pyridazin-3-yl; pyridazin-4-yl; 2-quinolinyl;3-quinolinyl; 4-quinolinyl; 1-isoquinolinyl; 3-isoquinolinyl; and4-isoquinolinyl; or substituted heterocycle, wherein the substituents(1-2 in number) are in any position and are independently selected fromthe group consisting of Br, Cl, F, R₁, and C(O)CH₃; R₃ are the same ordifferent and independently selected from the group consisting of: H;C₁-C₄-straight chain alkyl; C₃-C₄-branched chain alkyl; C₂-C₄-alkenylchain; (CH₂)_(n)Ph; and (CH₂)_(n)-substituted phenyl, wherein the phenylsubstituents are as defined above in R₂; R₄=H; C₁-C₄-straight chainalkyl; or C₃-C₄-branched chain alkyl; R₃ and R₄ can be linked togetherby a carbon chain to form with intervening atoms a 5-8-memberedsaturated or unsaturated ring; n1=0-3; n=0-3; A=CH₂; (CH₂)₂; (CH₂)₃;OCH₂CH₂; or CHCH₃; Y=H; OR₁; N(R₁)₂; N(R₁)C(O)R₃; N(R₁)C(O)R₅;N(R₁)C(O)CH(R₆)NH₂; N(R₁)SO₂R₃; N(R₁)C(O)NHR₃; or N(R₁)C(O)OR₆;R₅=C₃-C₇-cycloalkyl; R₆=C₁-C₄-straight chain alkyl; C₃-C₄-branched chainalkyl; C₂-C₄-alkenyl chain; (CH₂)_(n)Ph; or (CH₂)_(n)-substitutedphenyl, wherein the phenyl substituents are as defined above in R₂; or apharmaceutically acceptable salt thereof; said process comprising:reacting a first intermediate compound of the formula:

with a compound of the formula:

where V₁=NH₂; OH; or SH; under conditions effective to form the purinederivative compound.
 9. A process according to claim 8, wherein if Y isNHR₁, said process further comprises: reacting the purine derivativecompound with R₃C(O)C₁ or R₅C(O)C₁ or R₃SO₂C₁ or R₃NCO or R₆OC(O)C1under conditions effective to form a final product having the sameformula as the purine derivative compound except that Y is NR₁C(O)R₃ orNR₁C(O)R₅ or NR₁SO₂R₃ or NR₁C(O)NHR₃ or NR₁C(O)OR₆.
 10. A processaccording to claim 8 further comprising: reacting a second intermediatecompound of the formula:

with a compound of the formula R₁-Z under conditions effective to formthe first intermediate compound.
 11. A process according to claim 10further comprising: reacting a third intermediate compound of theformula:

with a compound of the formula 2,6-dichloropurine under conditionseffective to form the second intermediate compound.
 12. A processaccording to claim 11 further comprising: reacting a fourth intermediatecompound of the formula:

with a compound of the formula: R₂—B(OH)₂, R₂—Sn(n-Bu)₃, or R₂—Sn (Me)₃,or mixtures thereof, under conditions effective to form the thirdintermediate compound.
 13. A process according to claim 8, wherein thepurine derivative compound has the formula: